KR20070069136A - Sustained drug release composition demonstrating an ascending zero order release pattern, methods of manufacturing such a composition - Google Patents
Sustained drug release composition demonstrating an ascending zero order release pattern, methods of manufacturing such a composition Download PDFInfo
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- KR20070069136A KR20070069136A KR1020077004326A KR20077004326A KR20070069136A KR 20070069136 A KR20070069136 A KR 20070069136A KR 1020077004326 A KR1020077004326 A KR 1020077004326A KR 20077004326 A KR20077004326 A KR 20077004326A KR 20070069136 A KR20070069136 A KR 20070069136A
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- South Korea
- Prior art keywords
- drug
- layer
- formulation
- microencapsulated
- release
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Abstract
Description
본 발명은 연장된 치료기간 동안 치료 약물의 목적하는 효과를 유지하기 위한 방법 및 기구에 관한 것이다. 특히, 본 발명은 연장된 기간 동안 위장관내에서 오름차 방출 속도로 약물을 방출하는 방법 및 기구에 관한 것이다. 이 방법에 의해 약물의 투여기간 동안 연장된 치료기간 동안 목적하는 치료적 약물 효과를 충분히 유지할 수 있는 정도의 오름차 속도로 약물이 방출될 수 있다. The present invention relates to methods and apparatus for maintaining the desired effect of a therapeutic drug for an extended period of treatment. In particular, the present invention relates to a method and apparatus for releasing a drug at an ascending release rate in the gastrointestinal tract for an extended period of time. This method allows the drug to be released at an ascending rate that is sufficient to maintain the desired therapeutic drug effect for an extended period of treatment during the administration of the drug.
약리효과를 나타내기 위해서는 약물이 체내의 작용 부위에서 적절한 농도가 되도록 유효성을 갖도록 만들어져야 한다. 이러한 유효성은 적용된 약물의 양, 적용 부위로부터의 약물의 흡수율 및 흡수정도, 약물의 분포, 조직내에서의 결합 또는 위치화(localization), 약물의 생형질전환 및 배설을 포함하는 다양한 요인에 의하여 영향을 받는다. 약물 유효성에 관해 일반적으로 사용되는 인자 중 하나는 약물을 투여한 환자의 혈액 또는 혈장, 또는 다른 적절한 체액 또는 조직에서 수득되는 약물의 농도이다. 편의상, 상기 농도를 "혈장 약물 농도"라 하고, 임의의 적절한 체액 또는 조직에서 측정된 약물 농도를 포함한다. 혈장 약물 농도의 측정은 예를 들면, 상이한 약물 제형 및/또는 상이한 약물 적용 루트에 따른 비교 정보와 같은 유용한 정보를 제공한다. 또한, 많은 약물에 있어서 목적하는 약리 효과, 즉, 치료적 약물 효과, 및 목적하지 않는 약리 효과, 즉, 부작용을 포함하는 다양한 약물 효과는 특정 혈장 약물 농도 또는 혈장 약물 농도의 범위와 상호관련이 있다. In order to have a pharmacological effect, a drug must be made to be effective at an appropriate concentration at the site of action in the body. This effectiveness is influenced by a variety of factors, including the amount of drug applied, the rate of absorption and absorption of the drug from the site of application, the distribution of the drug, binding or localization within the tissue, biotransformation and excretion of the drug. Receive. One of the factors commonly used with regard to drug efficacy is the concentration of drug obtained in the blood or plasma of the patient administering the drug, or other suitable body fluid or tissue. For convenience, such concentrations are referred to as "plasma drug concentrations" and include drug concentrations measured in any suitable body fluid or tissue. Determination of plasma drug concentration provides useful information such as, for example, comparative information according to different drug formulations and / or different drug application routes. In addition, for many drugs, various drug effects, including desired pharmacological effects, ie, therapeutic drug effects, and undesired pharmacological effects, ie side effects, are correlated with a particular plasma drug concentration or a range of plasma drug concentrations. .
경구 투여용 약물 제형은, 위장관(GI)내에서 흡수가 일어나고 표면부, 혈류 및 (GI 트랙의 부분별로 현저하게 다양한) 막 특성, 약물 존재의 생리화학적 특성, 약물-특정 수송 메카니즘의 존재 및 활성 등과 같은 국소 미소 서식 환경(microenvironment)의 생리화학적 특성을 포함하는 많은 요인에 의해 영향을 받는다. 경구용 제형으로 투여되는 약물의 흡수 속도에 있어서 중요한 요인은 약물이 제형으로부터 방출되는 속도이다. 경구용 제형에서 약물 방출 속도는 전형적으로 시험관내(in vitro)에서의 용해 속도, 즉, 단위 시간 당 제형으로부터 방출되는 약물의 양으로 측정한다.Drug formulations for oral administration have absorption in the gastrointestinal tract (GI) and have surface properties, blood flow and membrane properties (significantly varied by part of the GI track), the physicochemical properties of the presence of the drug, the presence and activity of drug-specific transport mechanisms. It is influenced by many factors, including the physicochemical properties of the local microenvironment such as. An important factor in the rate of absorption of the drug administered in the oral dosage form is the rate at which the drug is released from the dosage form. The rate of drug release in oral formulations is typically determined by the rate of dissolution in vitro, ie the amount of drug released from the formulation per unit time.
통상 경구용 제형은 일반적으로 본질적으로 약물의 전체 용량이 매우 단시간내에 제형으로부터 방출되기 때문에 "속효성"으로 나타낼 수 있다. 방출된 약물의 이러한 볼루스가 흡수되면, 혈장 약물 농도는 보통 급속하게 최대 또는 피크 농도로 상승하며, 약물이 분배, 결합, 또는 조직내에 위치화, 생형질전환 및/또는 배설되면 그 결과 감소한다. 상기 감소기간은 약물 종류에 따라 다양하고 많은 요인에 의존하며, 감소기간은 특정 약물의 특성이 될 것이다. 일반적으로 혈장 약물 농도가 증가, 피크 도달 및 감소하는 기간의 특정 부분, 즉 혈장 약물 농도가 유효한 농도에 도달하거나 초과할 때 약물은 치료적 효과를 제공하게 된다. 또한, 상기 기 간 동안 특정 포인트, 즉 혈장 약물 농도가 유효 농도 이하로 감소하는 경우 치료 효과가 사라지게 된다. 또한, 피크 농도인 때 전후, 즉 혈장 약물 농도가 가장 높은 범위내에 있을 때 부작용이 나타날 수 있다. Oral formulations generally can be referred to as "fast-acting" because essentially the entire dose of drug is released from the formulation in a very short time. When this bolus of released drug is absorbed, the plasma drug concentration usually rises rapidly to a maximum or peak concentration and decreases as the drug is distributed, bound, or localized, biotransformed and / or excreted in the tissue. . The duration of reduction varies with the type of drug and depends on many factors, and the duration of reduction will be characteristic of the particular drug. In general, the drug will provide a therapeutic effect when certain parts of the period during which the plasma drug concentration increases, peaks reach, and decreases, that is, when the plasma drug concentration reaches or exceeds the effective concentration. In addition, if the specific point, that is, the plasma drug concentration decreases below the effective concentration during the period, the therapeutic effect disappears. In addition, side effects may occur before and after the peak concentration, ie, when the plasma drug concentration is within the highest range.
상기 측면에서, 혈장 약물 농도가 유효 혈장 약물 농도 범위 내에 있을 때 그 기간 동안 약물효과가 지속적으로 나타난다면 유용할 것이다. 혈장 약물 농도는 시간이 지나면 감소하므로, 속효성 약물 제형을 다중 용량으로 적절한 간격으로 투여해야만 혈중 약물 농도가 유효 농도 범위내에서 유지되거나 다시 상승하는 것을 보증할 수 있다. 반면 동시에, 혈중 약물 농도의 상승 및/또는 부작용이 일어나는 더 높은 범위에서 너무 오래 유지되는 것을 방지하거나 최소화하는 것이 필요하다. 따라서, 많은 약물의 경우, 목적하는, 목적하지 않는 약리 효과의 밸런스가 장기 치료기간 동안 만족스럽게 유지되기 위해서는 속효성 제형을 다중, 분할 용량으로 적절한 간격으로 투여하여야만 한다. In this respect, it would be useful if the drug effect continued to occur during that period when the plasma drug concentration was within the effective plasma drug concentration range. Since plasma drug concentration decreases over time, the fast-acting drug formulation should be administered at appropriate intervals in multiple doses to ensure that the blood drug concentration remains within the effective concentration range or rises again. At the same time, on the other hand, it is necessary to prevent or minimize the maintenance of too long in the higher ranges in which elevated blood levels and / or side effects occur. Thus, for many drugs, fast-acting formulations must be administered at appropriate intervals in multiple, divided doses in order for the desired balance of undesired pharmacological effects to be maintained satisfactorily for long term treatment.
약물 치료를 증대하기 위한 한 방편으로 제형으로부터 약물의 방출 속도를 변화시킴으로써 일차적으로 약물의 흡수에 영향을 주는 비-속효성 경구 약물 제형이 제공되었다. 상기 비-속효성 송달 시스템의 예는 지연 방출형 및 서방성 시스템을 포함한다. 서방성 제형은 일반적으로 속효성 제형과 비교할 때 연장된 기간동안 약물을 방출한다. 경구용 제형에서 서방성 약물을 제공하는 많은 접근법들이 기술분야에 알려져 있다. 이러한 접근법으로는 Remington's Pharmaceutical Sciences, 1990 ed., pp. 1682-168에 소개된 바와 같이, 예를 들면 저장소(reservoir) 기구 및 매트릭스 기구와 같은 확산 시스템, 캡슐화된 용해 시스템(예를 들면, "티니 타 임 정제"를 포함하는) 및 매트릭스 용해 시스템과 같은 용해 시스템 , 확산/용해 혼합 시스템, 삼투압 시스템 및 이온-교환 수지 시스템을 포함한다. 본 명세서에 인용된 모든 참고문헌은 그 전체 내용이 소개된 것과 같다고 본다.As a way to enhance drug treatment, non-acting oral drug formulations have been provided that primarily affect the absorption of the drug by varying the rate of release of the drug from the formulation. Examples of such non-rapid delivery systems include delayed release and sustained release systems. Sustained release formulations generally release the drug for an extended period of time as compared to fast-acting formulations. Many approaches for providing sustained release drugs in oral formulations are known in the art. Such an approach is described in Remington's Pharmaceutical Sciences, 1990 ed., Pp. As introduced in 1682-168, for example, diffusion systems such as reservoir and matrix devices, encapsulated dissolution systems (including, for example, “Tinitim tablets”) and matrix dissolution systems Dissolution systems, diffusion / dissolution mixing systems, osmotic systems, and ion-exchange resin systems. All references cited herein are deemed to have been incorporated in their entirety.
연장된 기간이상 실질적으로 일정한 방출 속도로 약물을 방출하는 서방성 경구용 제형을 제공하는 것이 특히 바람직하다. 이러한 방법으로, 많은 약물에서, 혈장 약물 농도가 초기에 약물 방출이 시작되었을 때 단시간내에 상승하고 그 후 일정 속도로 약물 방출이 유지되면서 연장된 기간 이상 실질적으로 일정하게 유지된다. 많은 약물에서, 이러한 실질적으로 일정한 혈장 약물 농도는 장기 치료 기간이상 약물의 일정한 유효성과 관련되어 있다. 또한, 초기에 혈장 약물 농도가 비교적 높은 피크가 되는 것을 방지할 수 있기 때문에 부작용이 거의 문제 되지 않을 수 있다. 따라서, 일정-방출 제형의 장점은 시간에 따른 투여가 필요한 약물 용량의 횟수가 줄어들고 약물의 목적하거나 목적하지 않는 약리 효과가 더 잘 조화된다는 점이다. It is particularly desirable to provide sustained release oral formulations that release the drug at a substantially constant release rate over an extended period of time. In this way, in many drugs, plasma drug concentrations rise substantially within a short time when drug release begins initially and then remain substantially constant over an extended period of time while drug release is maintained at a constant rate. In many drugs, this substantially constant plasma drug concentration is associated with a constant effectiveness of the drug over the long term treatment period. In addition, since the plasma drug concentration can be prevented from initially reaching a relatively high peak, side effects may be rarely a problem. Thus, the advantage of the constant-release formulation is that the number of doses of the drug requiring administration over time is reduced and the desired or undesired pharmacological effects of the drug are better coordinated.
비록 일정-방출 제형이 많은 다른 약물 치료에 있어 유효하다는 것이 증명 된 바 있으나, 완벽하게 만족스럽지는 않은 임상적 상황이 있다. 일정한 약물 방출이 실질적으로 유지되면 유효성이 지속될 것으로 기대되었으나, 어떤 증상 또는 질병에 대한 일정-방출 제형을 투여한 몇몇 환자에게서 지속되는 유효성을 제공하기 위해 기대되는 약물의 치료적 효과가 목적하는 치료 기간이 끝나기 전에 감소하는 것이 관찰되었다. 따라서, 다양한 패턴으로 송달을 조절하는 대체 수단의 제공이 요구된다. Although constant-release formulations have proven to be effective in many other drug treatments, there are clinical situations that are not completely satisfactory. Effectiveness was expected to persist if a constant drug release was substantially maintained, but the therapeutic effect of the drug expected to provide sustained efficacy in some patients who received a constant-release formulation for a symptom or disease is the desired duration of treatment. A decrease was observed before it was over. Thus, there is a need to provide alternative means of regulating delivery in various patterns.
연장된 기간동안 실질적으로 일정 속도로 약물을 방출하는 서방성 제형인 만족스럽지 않은 조건은 방출속도는 실질적으로 일정하기 보다는 오름차인 방출속도로 약물이 투여되었다. 전체적으로 만족스럽지 않은 연장된 기간동안 약물 방출의 실질적인 일정한 속도를 제공하는 서방성 경구용 제형으로 약물 치료를 하는 임상례로는 주의 결여 장애(Attention Deficit Disorder, ADD) 및 주의력 결핍 과다행동장애(Attention Deficit Hyperactivity Disorder, ADHD)를 포함하는 다양한 증상 및 장애를 치료하기 위한 중추신경계 흥분 약물의 사용이 있다.An unsatisfactory condition, which is a sustained release formulation that releases the drug at a substantially constant rate for an extended period of time, was administered at an ascending release rate rather than a substantially constant release rate. Clinical examples of drug therapy with sustained release oral dosage forms that provide a substantially constant rate of drug release over an extended period of unsatisfactory overall include Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity. There is the use of central nervous system excitatory drugs to treat various symptoms and disorders, including Disorder (ADHD).
미국 특허 출원 제 20010012847호(Lam 등)에 상기 증상 및 장애의 치료에 유용한 오름차 방출 속도 프로파일을 갖는 제형이 개시되어 있다.U.S. Patent Application No. 20010012847 (Lam et al.) Discloses formulations having an ascending release rate profile useful for the treatment of such symptoms and disorders.
오름차 속도의 방출을 제공하는 추가적 제형이 기술분야에 있어 또한 유용할 수 있다. 따라서, 상기 제형을 제조하고 사용하는 방법과 함께 적절한 연장된 기간 이상 상기 방출 속도를 제공하는데 적합한 서방성 매트릭스 경구용 제형의 필요성이 증가되었다. Additional formulations that provide release of ascending rates may also be useful in the art. Thus, there has been an increased need for sustained release matrix oral formulations that are suitable for providing the release rate over an appropriate prolonged period of time with the methods of making and using the formulations.
발명의 요약Summary of the Invention
일면에서, 본 발명은: (i) 중합체 매트릭스, 및 (ii) 마이크로캡슐화된 약물을 포함하는 지연층(여기에서 지연층은 비-마이크로캡슐화된 약물이 실질적으로 없다); (iii) 중합체 매트릭스, 및 (iv) 비-마이크로캡슐화된 약물 매트릭스를 포함하는 제2층(여기에서, 제2층은 지연층에 인접하여 위치한다)를 포함하는 약물의 서방성 제형과 관련된 것이다. In one aspect, the present invention provides a retardation layer comprising (i) a polymer matrix, and (ii) a microencapsulated drug, wherein the retardation layer is substantially free of non-microencapsulated drug; (iii) a sustained release formulation of a drug comprising a polymer matrix and (iv) a second layer comprising a non-microencapsulated drug matrix, wherein the second layer is located adjacent to the retardation layer. .
다른 일면에서, 본 발명은 (i) 중합체 매트릭스, 및 (ii) 마이크로캡슐화된 약물을 포함하는 지연층(여기에서 지연층은 비-마이크로캡슐화된 약물이 실질적으로 없다); (vii) 중합체 매트릭스, 및 비-마이크로캡슐화된 약물 매트릭스를 포함하는 제2층(여기에서, 제2층은 지연층에 인접하여 위치한다)를 포함하는 약물의 서방성 제형을 제조하는 방법과 관련된 것이다. In another aspect, the present invention provides a retardation layer comprising (i) a polymer matrix, and (ii) a microencapsulated drug, wherein the retardation layer is substantially free of non-microencapsulated drug; (vii) a method for preparing a sustained release formulation of a drug comprising a polymer matrix and a second layer comprising a non-microencapsulated drug matrix, wherein the second layer is located adjacent to the retardation layer. will be.
발명자들은 상기 언급한 바와 같은 이 기술분야의 문제점을 중합체 매트릭스, 비-마이크로캡슐화된 약물 및 마이크로캡슐화된 약물의 배합물을 사용하여 극복할 수 있다는 것을 예기치 못하게 발견하였다. 특히, 이 기술분야의 문제점은 중합체 매트릭스를 포함하는 지연층(여기에서, 지연층은 비-마이크로캡슐화된 약물 매트릭스가 실질적으로 없다); 및 중합체 매트릭스, 및 비-마이크로캡슐화된 약물 매트릭스를 포함하는 제2층 (여기에서 제2층은 지연층에 인접하여 위치한다)을 포함하는 서방성 약물 제형을 제공함으로써 극복할 수 있다. 구체예에서, 본 발명은 상기 제형과 관련이 있고, 여기에서 제2층에 존재하는 비-마이크로캡슐화된 약물의 중량에 대한 지연층에 존재하는 마이크로캡슐화된 약물의 중량비는 약 0.01:1 내지 약 10:1의 범위이다. The inventors have unexpectedly discovered that problems in the art as mentioned above can be overcome using a combination of polymer matrix, non-microencapsulated drug and microencapsulated drug. In particular, problems in the art include: retardation layers comprising a polymer matrix, wherein the retardation layer is substantially free of non-microencapsulated drug matrix; And a second layer comprising a polymer matrix and a non-microencapsulated drug matrix, wherein the second layer is located adjacent to the retardation layer. In an embodiment, the invention relates to the formulation wherein the weight ratio of the microencapsulated drug present in the retardation layer to the weight of the non-microencapsulated drug present in the second layer is from about 0.01: 1 to about In the range 10: 1.
특정 메커니즘에 한정되는 것은 아니나, 본 발명에 따른 제형으로부터의 약물 방출은 확산 및 부식(erosion)의 배합에 의한 작용일 것이다. 실험에서, 중합체 매트릭스는 미디아 침투에 의하여 수화하고 팽창한다. 이로 인해 중합체 매트릭스(건조 코어, 겔층 및 불용해된 겔층)내에 세 개의 유동 프론트: 팽창 프론트, 부식 프론트 및 확산 프론트가 나타나며 상이한 부위가 생긴다. 마이크로캡슐화된 약물을 첨가하면 비-마이크로캡슐화된 약물보다 느리게 방출되는 약물의 저장소를 제공하며, 이는 마이크로캡슐화 물질에 의해 도입된 수화 지연 때문이다. 그 후 제형으로부터 임의의 약물의 방출은 제형의 바로 그 표면에서 일어나는 매우 적은 양의 마이크로캡슐화된 및 비-마이크로캡슐화된 약물 입자를 제외하고, 중합체 매트릭스 겔층을 통한 약물 수송 뿐만 아니라, 중합체 완화, 팽창 및 용해에 의존한다. 일례에서, 중합체 매트릭스 물질 및 마이크로캡슐화된 물질은 중합체 매트릭스로부터 마이크로캡슐화된 약물의 방출속도 비율이 중합체 매트릭스로부터의 비-마이크로캡슐화된 약물의 방출보다 약 0.1 내지 약 3, 바람직하게는 약 0.5 내지 1.0 배 느린 범위에서 선택된다.Although not limited to specific mechanisms, drug release from the formulations according to the present invention will be effected by the combination of diffusion and erosion. In the experiment, the polymer matrix hydrates and expands by median infiltration. This results in three flow fronts: an expansion front, a corrosion front and a diffusion front in the polymer matrix (dry core, gel layer and insoluble gel layer) and different areas. The addition of the microencapsulated drug provides a reservoir of drug that is released more slowly than the non-microencapsulated drug because of the delay in hydration introduced by the microencapsulated material. The release of any drug from the formulation then results in polymer relaxation, swelling as well as drug transport through the polymer matrix gel layer, with the exception of very small amounts of microencapsulated and non-microencapsulated drug particles that occur on the very surface of the formulation. And dissolution. In one example, the polymeric matrix material and the microencapsulated material have a release rate ratio of the microencapsulated drug from the polymer matrix from about 0.1 to about 3, preferably about 0.5 to 1.0, than the release of the non-microencapsulated drug from the polymer matrix. It is selected in the 2x slow range.
또 다른 일례에서, 제형으로부터 약물의 전체 방출속도를 조정하기 위하여 서브-층과 같은 부가층이 본 제형에 포함될 수 있다. 예를 들면, 실질적으로 마이크로캡슐화되거나 마이크로캡슐화되지 않은 특정 양의 약물을 포함하거나 포함하지 않는 부가층은 제형 실험동안 다양한 시간대에서 제형으로부터 약물의 방출속도를 지연시키거나 감소시킬 수 있었다. 약물 방출에 영향을 줄 수 있는 다른 다양한 요소들(중합체 매트릭스 및 마이크로캡슐화 물질이 동일하게 남아있다고 가정할 때)에는 중합체 농도에 대한 약물의 비율(더 많은 중합체 및 더 적은 약물은 방출속도를 감소시킴), 및 제형 기하학(방출이 되는 표면적이 넓을수록 방출속도가 증가함)을 들 수 있다. 중합체 분자량이 감소하면 거대분자(macromolecule)의 얽힘(entanglement) 정도가 감소한다. 그러므로, 물 흡수팽윤시 중합체 사슬의 이동도는 증가한다. 이는 물 및 약물 확산률을 증가시키고, 약물 방출속도를 증가시킨다. In another example, additional layers, such as sub-layers, may be included in the formulation to adjust the overall release rate of the drug from the formulation. For example, an additional layer, with or without a particular amount of drug, which is substantially microencapsulated or not microencapsulated, could delay or reduce the release rate of the drug from the formulation at various times during the formulation experiment. Various other factors that can affect drug release (assuming the polymer matrix and microencapsulation material remain the same), ratio of drug to polymer concentration (more polymers and less drug reduce release rate). ) And formulation geometry (the higher the surface area to be released, the higher the release rate). Reducing the molecular weight of the polymer reduces the degree of entanglement of the macromolecules. Therefore, the mobility of the polymer chains increases upon water absorption swelling. This increases water and drug diffusion rates and increases drug release rates.
본 발명을 상세히 설명하기 전에, 달리 언급되어 있지 않은 한, 본 발명은 특정 약물, 부형제, 중합체, 염 등으로 제한되지 않고 이들은 물론 변경가능한 것임을 이해할 필요가 있다. 또, 본 명세서에 기재된 용어는 특정의 실시형태만을 설명할 목적일 뿐, 본 발명의 범위를 제한하기 위한 의도는 없는 것임을 이해할 필요가 있다. Before describing the invention in detail, it is to be understood that the invention is not limited to specific drugs, excipients, polymers, salts, etc., unless otherwise stated, and these are, of course, changeable. It is also to be understood that the terminology described herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
수치의 범위가 제공될 경우, 명백하게 규정되어 있지 않은 한, 그 범위의 상한치와 하한치 사이의 하한치의 1/10 단위로 각각의 사이에 있는 값 그리고 기타 달리 표현되거나 그 표현된 범위에 있어서 사이에 끼인 값은 본 발명에 포함되는 것으로 이해할 필요가 있다. 이들 보다 작은 범위의 상한치와 하한치는 독립적으로 보다 작은 범위 내에 포함될 수도 있고, 또한 표시된 범위 내에서 구체적으로 제외된 한계에 종속되는 본 발명의 범위 내에 포함되는 것이다. 표시된 범위가 한계치의 한쪽 또는 양쪽을 포함할 경우, 포함된 한계치의 어느 한쪽 또는 양쪽을 제외한 범위도 본 발명에 포함된다. When a range of values is provided, unless otherwise specified, the values between each other in one tenths of the lower limit between the upper and lower limits of the range and otherwise expressed or sandwiched in the expressed range. It is necessary to understand that a value is included in this invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges, and are also included within the scope of the present invention, subject to the limits specifically excluded within the indicated ranges. When the indicated range includes one or both of the limits, the range excluding either or both of the included limits is also included in the present invention.
비록 본 발명은 목적하는 치료효과를 제공하기 위한 특정예의 약물을 포함하는 일례의 제형, 상기 제형을 제조하는 방법 및 토피라메이트(topiramate), 팔리페리돈 및 리스페리돈-함유 제형을 사용하는 방법에 의해 설명되어 있으나, 본 발명은 실시예에 의해 한정되지 않는다. 본 발명은 넓게는 여기에 소개된 관점에서 이 기술분야의 기술자에게 명백하게 되는 바와 같이 목적하는 연장된 기간동안 임의의 적절한 약물 및 약물치료에 관하여 치료효과를 유지하기 위하여 연장된 기간동안 오름차 약물방출속도를 제공하는 경구용 서방성 제형, 상기 제형을 제조하는 방법 및 상기 제형을 사용하는 방법을 포함한다. Although the invention is described by way of example formulations comprising specific examples of drugs to provide the desired therapeutic effect, methods of making such formulations and methods of using topiramate, paliperidone and risperidone-containing formulations However, the present invention is not limited by the embodiment. The invention broadly ascends the rate of drug release over an extended period of time to maintain the therapeutic effect with respect to any suitable drug and drug treatment for the desired extended period of time as will be apparent to those skilled in the art in view of the teachings herein. Oral sustained release formulations to provide a method of making the formulations and methods of using the formulations.
"오름차 방출속도"는 연장된 기간에 걸쳐서 연속적으로 또한 점차적으로 증가하는, 증분 단위시간 당 분배된 약물의 양을 의미한다. 바람직하게는, 시간의 함수로서의 약물 방출속도는(단차 방식보다는 오히려) 항정(steady) 방식으로 증가한다. 더욱 바람직하게는, 오름차 방출 속도는 다음과 같은 특징을 지닐 수 있다. 제형에 대한 시간의 함수로서의 방출속도는 방출약물 % 대 시간으로서 또는 방출약물의 mg/hr(시간에 대해)로 측정해서 플롯한다. 오름차 방출속도는, 약 2 내지 12시간, 바람직하게는 약 2시간 내지 약 18시간, 더욱 바람직하게는 약 4시간 내지 약 12시간, 더욱 바람직하게는 약 4시간 내지 약 18시간의 기간에 걸쳐 이전의 2시간 간격에 비해서 높은 2시간 간격 동안의 약물의 mg/시간으로 표시된 평균속도를 특징으로 한다. 바람직하게는, 평균속도의 증가는 용량의 30% 미만이 임의의 2시간 간격 동안 방출되도록, 더욱 바람직하게는 용량의 25% 미만이 임의의 2시간 간격 동안 방출되도록 점진적이다. 바람직하게는 오름차 방출속도는 제형 중의 약물의 적어도 50%, 더욱 바람직하게는 적어도 75%가 방출될 때까지 유지된다. 일례에서, 지연층에 존재하는 마이크로캡슐화된 약물의 중량에 대한 제2층에 존재하는 비-마이크로캡슐화된 약물의 중량비는 T25까지 총 약물 중량의 약 10% 내지 약 40%가 방출, T50까지 총 약물 중량의 약 40% 내지 약 65%가 방출, T75까지 총 약물 중량의 약 65% 내지 약 85%가 방출, 및 T90까지 총 약물 중량의 약 85% 내지 90%가 방출되는 것에서 선택된다. "Rising rate of release" means the amount of drug dispensed per incremental unit of time, which increases continuously and gradually over an extended period of time. Preferably, the rate of drug release as a function of time increases in a steady manner (rather than a stepwise manner). More preferably, the ascending release rate may have the following characteristics. The release rate as a function of time for the formulation is plotted as a percent release drug versus time or measured in mg / hr (relative to time) of the release drug. The ascending release rate is transferred over a period of about 2 to 12 hours, preferably about 2 hours to about 18 hours, more preferably about 4 hours to about 12 hours, more preferably about 4 hours to about 18 hours. It is characterized by the average rate expressed in mg / hour of the drug during the high two hour interval compared to the two hour interval. Preferably, the increase in average rate is gradual such that less than 30% of the dose is released during any 2 hour interval, more preferably less than 25% of the dose is released during any 2 hour interval. Preferably the ascending release rate is maintained until at least 50%, more preferably at least 75% of the drug in the formulation is released. In one example, the weight ratio of the non-microencapsulated drug present in the second layer to the weight of the microencapsulated drug present in the retardation layer is about 10% to about 40% of the total drug weight released up to T25, totaling up to T50 From about 40% to about 65% of the drug weight released, from about 65% to about 85% of the total drug weight up to T75, and from about 85% to 90% of the total drug weight up to T90.
측정된 주기적 방출속도, 예를 들면 t=1 시간(0과 같지 않은)에서의 주기적 방출속도는 선행하는 기간, 예를 들면 제형이 투여되기 전 시간동안의 방출속도보다 항상 더 클 수 있으며, 그러므로 최초 주기적 방출속도는 항상 오름차 방출속도를 나타낸다. 본 명세서의 예에 언급된 오름차 방출속도는: 약물의 서방성을 제공하기 위해 적합한 제형으로부터의 방출속도 및 또한 서방성 구성요소를 위한 초기 속효성 구성요소인 일정량의 약물을 부가적으로 포함하는 예들에서의 방출속도를 말한다. 그러므로, 다른 일례에서, 초기 약물 피크 다음 방출속도를 측정하면, 선행 기간동안의 방출속도보다 더 클 것이다. 본 발명은 또한 기초를 이루는 제형 위에 코팅되어 적용되는 속효성 용량의 약물을 부가적으로 포함하는 제형예에 적용되며, t=1시간에서 측정된 약물 방출은 속효성 약물 코팅으로부터 방출된 약물 및 기초를 이루는 제형으로부터 방출되는 약물을 일반적으로 모두 반영할 수 있으나, 약물 오버코트로부터 방출되는 약물의 양은 t=2시간일 때의 약물 방출속도가 t=1 시간일 때 약물 방출속도보다 더 큰지 여부를 결정하는 데 있어서는 무시된다. The measured periodic release rate, e.g., the periodic release rate at t = 1 hour (not equal to 0), can always be greater than the release rate during the preceding period, e.g., the time before the formulation is administered. The initial periodic release rate always represents the ascending release rate. The ascending release rate referred to in the examples herein includes: in examples that additionally include a release rate from a suitable formulation to provide sustained release of the drug and also a quantity of drug that is an initial fast-acting component for the sustained release component. The release rate of Therefore, in another example, measuring the release rate following the initial drug peak would be greater than the release rate during the preceding period. The invention also applies to formulations which additionally comprise a fast-acting dose of a drug that is coated and applied onto the underlying formulation, wherein drug release measured at t = 1 hour results in the drug and the underlying drug released from the fast-acting drug coating. Although generally all of the drug released from the formulation can be reflected, the amount of drug released from the drug overcoat is used to determine whether the drug release rate at t = 2 hours is greater than the drug release rate at t = 1 hour. It is ignored.
오름차 방출속도가 제공되는 기간을 나타내기 위해 사용되는 "연장된 기간"은 t=0시간에 시작하여 적어도 제형의 T.sub.90에 상응하는, 중간포인트까지 계속되는 기간, 바람직하게는 중간포인트이상 계속되는 기간을 의미한다. 왜냐하면, 본 발명의 제형은 본 발명의 목적에 적합한 T.sub.90은 적어도 약 6시간이고, 결과적으로 "연장된 기간"은 오름차 방출속도가 적어도 3시간인 서방성 약물이 제공되는 것을 의도하기 때문이다. The “extended period” used to indicate the period during which the ascending release rate is provided is a period starting at t = 0 hours and continuing at least to the midpoint, corresponding to at least T.sub.90 of the formulation, preferably above the midpoint. It means a continuous period. Because the formulation of the present invention is intended to provide a sustained release drug having a T.sub.90 suitable for the purposes of the present invention for at least about 6 hours and consequently an "extended period" of ascending release rate of at least 3 hours. Because.
"오름차 약물 혈장 농도"는 초기 용량을 준 후 처음 약 24시간 정도에서의 약물 혈장 농도 프로파일을 의미하며, 여기에서 프로파일은 최대 농도로 증가하는 양상을 띄고, 여기에서 상기 최대는 초기 용량을 준 후 약 6시간, 바람직하게는 약 8시간, 더욱 바람직하게는 12시간 이후에 도달한다. "Rising drug plasma concentration" means the drug plasma concentration profile at about 24 hours after the initial dose is given, where the profile increases to the maximum concentration, where the maximum is after the initial dose is given. About 6 hours, preferably about 8 hours, more preferably 12 hours later.
"지연층"은 적어도 부분적으로 제형으로부터 약물의 방출을 지연시키기 위한 기능을 하는 층을 의미한다."Delay layer" means a layer that at least partially functions to delay the release of the drug from the formulation.
"송달하다" 및 "송달"은 제형으로부터 약제가 분리되는 것을 나타내며, 여기에서 약제는 사용된 주변 용액에 용해될 수 있는 것이다. "Deliver" and "delivery" refer to the separation of a medicament from a formulation, wherein the medicament is soluble in the surrounding solution used.
"제형"은 중합체, 현탁제, 계면활성제, 붕해제, 용해 조절제, 결합제, 희석제, 윤활제, 안정화제, 항산화제, 삼투제, 착색제, 가소제, 코팅 등과 같은 약제학적으로 허용가능한 부형제를 임의로 함유하는 조성물 및 기구를 포함하는 약제학적 조성물 또는 장치(기구)를 의미한다. "Formulation" optionally contains pharmaceutically acceptable excipients such as polymers, suspending agents, surfactants, disintegrants, dissolution regulators, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings, and the like. By pharmaceutical composition or device (apparatus) comprising the composition and apparatus.
"약물"은 약제학적으로 활성있는 제제 또는 약제학적으로 허용가능한 그들의 염을 의미한다. 본 발명에서 사용되는 약물은 이에 한정되는 것은 아니나: 프로클로퍼진 에디실레이트(prochlorperzine edisylate), 황산 제1철(ferrous sulfate), 아미노카프로산(aminocaproic acid), 메카밀아민 하이드로클로라이드(mecamylamine hydrochloride), 프로카인아미드 하이드로클로라이드(procainamide hydrochloride), 암페타민 설페이트(amphetamine sulfate), 메트암페타민 하이드로클로라이드(methamphetamine hydrochloride), 벤즈암페타민 하이드로클로라이드(benzamphetamine hydrochloride), 이소프로테레놀 설페이트(isoproterenol sulfate), 펜메트라진 하이드로클로라이드(phenmetrazine hydrochloride), 베타네콜 클로라이드(bethanechol chloride), 메타콜린 클로라이드(methacholine chloride), 필로카핀 하이드로클로라이드(pilocarpine hydrochloride), 아트로핀 설페이트(atropine sulfate), 스코폴아민 브로마이드(scopolamine bromide), 이소프로파미드 요다이드(isopropamide iodide), 트리디헥세틸 클로라이드(tridihexethyl chloride), 펜포민 하이드로클로라이드(phenformin hydrochloride), 메틸페니데이트 하이드로클로라이드(methylphenidate hydrochloride), 테오필린 콜리네이트(theophylline cholinate), 세팔렉신 하이드로클로라이드(cephalexin hydrochloride), 디페니돌(diphenidol), 메클리진 하이드로클로라이드(meclizine hydrochloride), 프로클로페라진 말레이트(prochlorperazine maleate), 페녹시벤자민(phenoxybenzamine), 티에틸퍼진 말레이트(thiethylperzine maleate), 아니신돈(anisindone), 디페나디온 에리트리틸 ㅌ테트라니트레이트(phenadione erythrityl tetranitrate), 디곡신(digoxin), 이소플루로페이트(isoflurophate), 아세타졸아미드(acetazolamide), 메타졸아미드(methazolamide), 벤드로플루메티아지드(bendroflumethiazide), 클로로프로마이드(chloropromaide), 톨라자미드(tolazamide), 클로마디논 아세테이트(chlormadinone acetate), 페나글리코돌(phenaglycodol), 알로푸리놀(allopurinol), 알루미늄 아스피린(aluminum aspirin), 메토트렉세이트(methotrexate), 아세틸 설피속사졸(acetyl sulfisoxazole), 에리스로마이신(erythromycin), 토피라메이트(topiramate), 팔리페리돈(paliperidone), 리스페리돈(risperidone), 옥시부티닌(oxybutynin), 메틸 페니데이트(methyl phenidate), 하이드로코티손(hydrocortisone), 하이드로코티코스테론 아세테이트(hydrocorticosterone acetate), 코티손 아세테이트(cortisone acetate), 덱사메타손(dexamethasone) 및 베타메타손, 트라임시놀론, 메틸테스토스테론, 17-S-에스트라디올, 에티닐 에스트라디올, 에티닐 에스트라디올 3-메틸 에테르, 프레드니솔론, 17-.varies.하이드로코티코스테론 아세테이트, 19-노르프로게스테론, 노르게스테롤, 노레틴드론, 노레티스테론, 노레티에데론, 프로게스테론, 노르게스테론, 노레티노드렐과 같은 그의 유도체, 아스피린, 아세트아미노펜, 인도메타신, 나프록센, 페노프로펜, 술린닥, 인도프로펜, 니트로글리세린, 이소소비드 디나이트레이트, 프로파놀롤, 티몰롤, 아테놀롤, 알프레놀롤, 시메티딘, 클로니딘, 이미프라민, 레보도파, 클로프로마진, 메틸도파, 디하이드록시페닐알라닌, 테오필린, 칼슘 글루코네이트, 케토프로펜, 이부프로펜, 세팔렉신, 에리스로마이신, 할로페리돌, 조메피락, 페러스 락테이트, 빈크아민, 디아제팜, 페녹시벤자민, 딜티아젬, 밀리논, 카프로프릴, 만도, 콴벤즈, 하이드로클로로티아지드, 라니티딘, 플루비프로펜, 페누펜(fenufen), 플루프로펜(fluprofen), 톨메틴, 알클로페낙, 메페나믹, 플루페나믹, 디푸이날(difuinal), 니모디핀, 니트렌디핀, 니솔디핀, 니카디핀, 펠로디핀, 리도플라진, 티아파밀, 갈로파밀, 암로디핀, 미오플라진, 리시놀프릴, 에날라프릴, 에날라프릴라트, 캡토프릴, 라미프릴, 파모티딘, 니자티딘, 수크랄페이트, 에틴티딘, 테트라톨롤, 미녹시딜, 클로디아제폭시드, 디아제팜, 아미트립틸린, 이미프라민, 및 테라조신 HCL 디-하이드레이트를 포함한다. 또 다른 예는 단백질 및 펩티드인데, 비한정적 예로: 인술린, 콜치신, 글루카곤, 갑상선 자극 호르몬, 부갑상선 및 뇌하수체 호르몬, 칼시토닌, 레닌, 프로락틴, 코티코트로핀, 타이로트로픽 호르몬(thyrotropic hormone), 여포자극호르몬, 융모성생식선자극호르몬, 생식선자극호르몬(gonadotropin releasing hormone), 소의 소마토트로핀, 돼지의 소마토트로핀, 옥시토신, 바소프레신, GRF, 프로락틴, 소마토스타틴, 리프레신, 판크레오지민, 황체형성 호르몬, LHRH, LHRH 효능제 및 길항제, 루프롤리드(leuprolide), 인터페론, 인터루킨, 인간 성장호르몬, 소의 성장 호르몬 및 돼지의 성장호르몬과 같은 성장호르몬, 프로스타글란딘, 생식 촉진제, 성장호르몬, 응고인자, 인간 이자 호르몬 분비 팩터(human pancreas hormone releasing factor), 아날로그 및 이들 화합물의 유도체와 같은 생식 저해제, 및 이들의 약제학적으로 허용되는 염 또는 그들의 아날로그 또는 유도체, 및 이들의 다양한 배합물, 및 상기 화합물의 다양한 약제학적으로 허용되는 염형태의 이들 화합물의 다양한 배합물을 포함한다. "Drug" means a pharmaceutically active agent or a pharmaceutically acceptable salt thereof. Drugs used in the present invention are not limited thereto: prochlorperzine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride , Procainamide hydrochloride, amphetamine sulfate, metamphetamine hydrochloride, benzampetamine hydrochloride, isoproterenol sulfate, isopraterenol sulfate, phenmethazine hydrochloride Phenmetrazine hydrochloride, betacholchol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropa Isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholinate, cephalexin hydrochloride (cephalexin hydrochloride) hydrochloride, diphenidol, meclizine hydrochloride, procloperazine maleate, phenoxybenzamine, thiethylperzine maleate, anicindon (anisindone), diphenadione erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide, metazolamide, bendrofluamide Methazide (bendroflumethiazide), chloropromaide, tolazamide, Chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, erythromycin Topiramate, paliperidone, risperidone, risperidone, oxybutynin, methyl phenidate, hydrocortisone, hydrocorticosterone acetate, cortisone acetate ( cortisone acetate), dexamethasone and betamethasone, triimcinolone, methyltestosterone, 17-S-estradiol, ethynyl estradiol, ethynyl estradiol 3-methyl ether, prednisolone, 17-.varies. hydrocorticosterone Acetate, 19-norprogesterone, norgesterol, noretin drone, noretysterone, norethiedrone, Derivatives thereof, such as progesterone, norgesterone, and noretinodrel, aspirin, acetaminophen, indomethacin, naproxen, phenopropene, sulindac, indopropene, nitroglycerin, isosorbide nitrate, propa Norolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, clopromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin , Haloperidol, jomepirak, ferus lactate, vinamine, diazepam, phenoxybenzamine, diltiazem, milnin, capropryl, mando, quanbenz, hydrochlorothiazide, ranitidine, flubiprofen, feh Nufenen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuinal, nimodipine, nirenedipine, nisoldipine, nikadipine, felodipine,Dopazine, thiopamyl, galofamil, amlodipine, myopazine, ricinolpril, enalapril, enalapril, captopril, ramipril, famotidine, nizatidine, sucralate, ethyntidine, tetra Tolol, minoxidil, clodiazepoxide, diazepam, amitriptyline, imipramine, and terrazosin HCL di-hydrate. Other examples are proteins and peptides, including but not limited to insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, lenin, prolactin, corticotropin, thyrotropic hormone, follicles Stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine somatotropin, swine somatotropin, oxytocin, vasopressin, GRF, prolactin, somatostatin, ripressin, pancregiomine, corpus luteum formation Hormones, LHRH, LHRH agonists and antagonists, leuprolide, interferon, interleukin, human growth hormone, bovine growth hormone and growth hormones such as pig growth hormone, prostaglandins, reproductive promoters, growth hormone, coagulation factors, humans Low reproductive effects such as human pancreas hormone releasing factor, analogues and derivatives of these compounds Releases, and their pharmaceutically acceptable salts or analogs or derivatives thereof, and various combinations thereof, and various combinations of these compounds in various pharmaceutically acceptable salt forms of the compounds.
"속효성 제형"은 투여 후 단시간 내에, 즉 일반적으로 수분 내지 약 1 시간 내에 약물을 실질적으로 완전히 방출하는 제형을 의미한다. "Short-acting formulation" means a formulation which releases the drug substantially completely within a short time after administration, ie generally within a few minutes to about 1 hour.
"매트릭스"는 특히 주변 및/또는 모양면에서, 지탱하거나 구조를 이루는 새로운 제형의 요소를 의미한다.By "matrix" is meant an element of a new formulation which is supported or structured, especially in terms of surroundings and / or shape.
본 명세서 중의 "환자"는 질병 또는 장애 치료가 필요한 동물, 전형적으로 포유류, 더욱 전형적으로 인간을 의미한다. "Patient" as used herein means an animal, typically a mammal, more typically a human, in need of treating a disease or disorder.
다른 언급이 없는 한 여기에 사용된 "약학적으로 허용되는 염"은 음이온 또는 양이온이 염의 약리학적 활성 또는 독성에 크게 기여하지 않으며 그 자체로 화합물의 염기의 약리학적 등가물인 그들 염을 의미한다. 염 형성의 목적을 위해 유용한 약제학적으로 허용가능한 산의 예로 염산, 황산, 푸마르산, 말레산, 숙신산, 아세트산, 벤조산, 시트르산, 타르타르산, 카본산 또는 인산; 및 염 형성의 목적을 위해 유용한 약제학적으로 허용가능한 염기의 예로, 알칼리금속염, 예를 들면 소디움 또는 포타시움 염; 알칼리토금속염, 예를 들면 칼슘 또는 마그네슘 염; 및 적절한 유기 리간드와 함께 형성되는 염, 예를 들면 4차 암모늄 염을 포함한다. Unless stated otherwise, as used herein, "pharmaceutically acceptable salts" refers to those salts in which the anion or cation does not contribute significantly to the pharmacological activity or toxicity of the salt and is itself a pharmacological equivalent of the base of the compound. Examples of pharmaceutically acceptable acids useful for the purpose of salt formation include hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carboxylic acid or phosphoric acid; And pharmaceutically acceptable bases useful for the purpose of salt formation, such as alkali metal salts, such as sodium or potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; And salts formed with suitable organic ligands, such as quaternary ammonium salts.
그러므로, 대표적인 약제학적으로 허용되는 염의 비한정적인 예로: 아세테이트, 벤젠술포네이트, 벤조에이트, 비카보네이트, 비설페이트, 비타르트레이트, 보레이트, 브로미드, 칼슘 에데테이트, 캄실레이트, 카보네이트, 클로라이드, 클라불라네이트, 시트레이트, 디하이드로클로라이드, 에데테이트, 에디실레이트, 에스톨레이트, 에실레이트, 푸마레이트, 글루세프테이트, 글루코네이트, 글루타메이트, 글리콜릴아르사닐레이트, 헥실레소시네이트, 하이드라바민, 하이드로브로미드, 하이드로클로라이드, 하이드록시나프토에이트, 요다이드, 이소티오네이트, 락테이트, 락토비오네이트, 라우레이트, 말레이트, 말레에이트, 만델레이트, 메실레이트, 메틸브로미드, 메틸니트레이트, 메틸설페이트, 무케이트, 나프실레이트, 니트레이트, N-메틸글루카민 암모늄 염, 올레에이트, 파모에이트(엠보네이트), 팔미테이트, 판토테네이트, 포스페이트/디포스페이트, 폴리갈락투로네이트, 살리실레이트, 스테아레이트, 설페이트, 서브아세테이트, 숙시네이트, 탄네이트, 타르트레이트, 테오클레이트, 토실레이트, 트리에티오디드, 발레레이트 및 이들의 배합물을 포함한다. Thus, non-limiting examples of representative pharmaceutically acceptable salts are: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, chamlate, carbonate, chloride, cla Bulanate, Citrate, Dihydrochloride, Edetate, Edicylate, Estoleate, Ecylate, Fumarate, Glucetate, Gluconate, Glutamate, Glycol arsanylate, Hexyl socinate, Hydrabamine , Hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, maleate, maleate, mandelate, mesylate, methyl bromide, methylnitrate , Methylsulfate, free, naphsylate, nitrate, N-methylglucamine Monium salts, oleates, pamoates (emcarbonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, subacetates, succinates, tanates, tarts Latex, theocate, tosylate, triethoxide, valerate and combinations thereof.
약제학적으로 허용되는 염의 제조에 사용될 수 있는 대표적인 산 및 염기로: 아세트산, 2,2- 디클로로악트산(2,2-dichloroactic acid), 아실레이티드 아미노산, 아디프산, 알긴산, 아스코르브산, L-아스파르트산, 벤젠술폰산, 벤조산, 4-아세트아미도벤조산, (+)-캄포산, 캄포설폰산, (+)-(1S)-캄포-10-설폰산, 카프산, 카프로산, 카프릴산, 신남산, 시트르산, 시클람산, 도데실설푸르산, 에탄-1,2-디술폰산, 에탄술폰산, 2-하이드로시-에탄설폰산(2-hydrocy-ethanesulfonic acid), 포름산, 푸마르산, 갈락타르산, 겐티스산(gentisic acid), 글루코헵톤산, D-글루콘산, D-글루코론산, L-글루탐산, a-옥소-글루타르산, 글리콜산, 히푸르산, 하이드로브롬산, 하이드로클로르산, (+)-L-락트산, (±)-DL-락트산, 락토비온산, 말레산, (-)-L-말산, 말론산, (±)-DL-만델산, 메탄술폰산, 나프탈렌-2-술폰산, 나프탈렌-1,5-디술폰산, 1-하이드록시-2-나프토산, 니코틴산, 질산, 올레산, 오로트산, 옥살산, 팔미트르산, 파모산, 포스포르산, L-피로글루탐산, 살리실산, 4-아미노-살리실산, 세바산, 스테아르산, 숙신산, 황산, 탄산(tannic acid), (+)-L-타르타르산, 티오시안산, p-톨루엔술폰산 및 운데실렌산을 포함하는 산; 및 암모니아, L-아르기닌, 베네타민, 벤자틴, 칼슘 하이드록시드, 콜린, 데아놀, 이데타놀아민, 디에틸아민, 2-(디에틸아미노)-에탄올, 에탄올아민, 에틸렌디아민, N-메틸-글루카민, 하이드라바민, 1H-이미다졸, L-리신, 마그네슘 하이드록시드, 4-(2-하이드록시에틸)-모르폴린, 피페라진, 포타시움 하이드록시드, 1-(2-하이드록시에틸)-피롤리딘, 2차 아민, 소디움 하이드록시드, 트리에탄올아민, 트로메타민 및 산화아연을 포함하는 염기, 및 이들의 배합물을 포함한다. Representative acids and bases that may be used in the preparation of pharmaceutically acceptable salts are: acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L -Aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphor acid, camphorsulfonic acid, (+)-(1S) -campo-10-sulfonic acid, capric acid, caproic acid, capryl Acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactar Acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucolic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hypofuric acid, hydrobromic acid, hydrochloric acid , (+)-L-lactic acid, (±) -DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2 -Sulfonic acid, naph Talen-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4 Acids including amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; And ammonia, L-arginine, benetamine, benzatin, calcium hydroxide, choline, deanol, idetanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N- Methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, potassium hydroxide, 1- (2-hydroxy Oxyethyl) -pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine and bases including zinc oxide, and combinations thereof.
"중합체"는 수화시, 점성의 젤라틴성 표면 장막 또는 겔층을 형성하고, 제형의 중심으로의 용액의 침투 및 중심으로부터의 약물의 방출을 조절하는 천연 및 합성 중합체를 포함한다. 임의의 일례에서, 이러한 겔층에 수반되는 생리화학적 특성으로는 제형으로부터의 수분 흡수 및 약물방출 메카니즘을 조절하는 것이 있다. 비록 바깥층으로부터 용해성 약물이 급격하게 방출될 수 있지만, 약물을 함유한 표면이 용해 미디아중에 노출되면 겔층을 통한 약물의 확산 또는 겔의 점진적인 부식에 의해 약물 방출이 시간에 따라 조절된다. 확산은 수용성 약물 방출을 조절하는 주요한 메카니즘이며, 매트릭스의 부식은 수불용성 약물의 방출을 조절하는 주요 메카니즘이다. 반면, 일반적으로 약물의 방출은 상기 두 메카니즘에 의해 일어날 것이다. "Polymers" include natural and synthetic polymers that, upon hydration, form a viscous gelatinous surface membrane or gel layer and control the penetration of the solution into the center of the formulation and the release of the drug from the center. In certain instances, the physicochemical properties involved in such gel layers include controlling the absorption of water from the formulation and the drug release mechanism. Although soluble drugs can be released rapidly from the outer layer, when the surface containing the drug is exposed to dissolved media, drug release is controlled over time by diffusion of the drug through the gel layer or gradual corrosion of the gel. Diffusion is a major mechanism for controlling the release of water soluble drugs, and corrosion of the matrix is a major mechanism for controlling the release of water insoluble drugs. On the other hand, in general, the release of the drug will be caused by the two mechanisms.
적절한 중합체의 비한정적 예로: 메틸 셀룰로즈, 하이드록시프로필 메틸셀룰로즈, 하이드록시에틸 셀룰로즈, 하이드록시프로필 셀룰로즈, 하이드록시에틸 메틸셀룰로즈, 카복시 메틸셀룰로즈 및 소디움 카복시 메틸셀룰로즈와 같은 친수성 셀룰로즈 유도체; 폴리비닐피롤리돈, 폴리에틸렌 옥사이드; 및 폴리사카라이드를 포함한다. 바람직한 중합체로는 하이드록시프로필 메틸셀룰로즈(HPMC) 및 이들의 유도체가 있다. Non-limiting examples of suitable polymers include: hydrophilic cellulose derivatives such as methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxy methylcellulose and sodium carboxy methylcellulose; Polyvinylpyrrolidone, polyethylene oxide; And polysaccharides. Preferred polymers include hydroxypropyl methylcellulose (HPMC) and derivatives thereof.
HPMC 유도체는 낮은, 정상 또는 높은 점도 등급으로 입수가능하다. 중합체의 점도는 제제로부터의 약물의 방출속도를 조절한다. 가장 적절한 특정 HPMC로는 메토셀 K100M, K15M, F4M, E4M, K4M, K100LV, K3, E15LV, E15LN, E15CLV, E50, E5 및 E3 (다우 케미컬, Midland Ml에서 입수가능)를 들 수 있다. 가장 바람직한 것은 메토셀 K100M이다.HPMC derivatives are available in low, normal or high viscosity grades. The viscosity of the polymer controls the rate of release of the drug from the formulation. The most suitable specific HPMCs include Methocel K100M, K15M, F4M, E4M, K4M, K100LV, K3, E15LV, E15LN, E15CLV, E50, E5 and E3 (available from Dow Chemical, Midland Ml). Most preferred is methocel K100M.
"중합체 및 비-마이크로캡슐화된 약물 매트릭스"는 중합체 및 비-마이크로캡슐화된 약물을 포함하는 매트릭스를 의미한다. "Polymeric and non-microencapsulated drug matrix" means a matrix comprising a polymer and a non-microencapsulated drug.
"중합체 매트릭스"는 중합체를 포함하는 매트릭스를 의미한다."Polymer matrix" means a matrix comprising a polymer.
"마이크로캡슐화된 약물"은 마이크로캡슐화 물질에 의해 캡슐화된 약물입자를 의미한다. 상기 물질의 비한정적 예로는 단백질, 폴리사카라이드, 전분, 왁스, 지방, 천연 및 합성 중합체, 및 수지 및/또는 이들의 배합물을 포함한다. 바람직한 일례에서, 마이크로캡슐화된 물질은 합성 중합체이고, 바람직하게는 에틸 아크릴레이트-메틸 메트아크릴레이트 공중합체이다. 마이크로캡슐화된 약물을 제조하는 적합한 방법의 비한정적 예로 유동화된 베드 코팅, 분무 건조, 분무 냉각(spray chilling), 스피닝 디스크 코팅(spinning disk coating), 고정 노즐 공유압출성형(stationary nozzle coextrusion), 해교(peptization), 원심성 해드 공유압출성형(centrifugal head coextrusion), 액침 노즐 공유압출성형(submerged nozzle coextrusion), 팬 코팅(pan coating), 용매 증발법(solvent evaporation), 코아세르베이션(coacervation, 단순 및 복합) 및 상분리법(phase separation), 계면중합(interfacial polymerization), in-situ 중합, 리포좀 기술(liposome technology) 및 나노캡슐기술(nanoencapsulation)을 포함한다. 바람직한 일례는 유동화 베드 코팅이다. 본 발명의 실시에 유용한 부가적 기술 및 물질의 비한정적 예로는 PJ 왓츠 등, 유화/용매 증발법에 사용되는 마이크로캡슐화(Microencapsulation using emulsification/solvent evaporation: an overview of techniques and applications, Crit Rev Ther Drug Carrier Syst.) 1990;7(3):235~ 59; 조절되는 경구용 약물 송달 시스템을 위한 마이크로캡슐; 미국 특허 5,362,424 (1994.11.8. 등록); 마이크로캡슐화 방법 및 그로부터 얻어진 생성물(Microencapsulation process and products therefrom), 미국 특허 5,407,609, 타이스 등, 1995.4.18. 등록; 생분해성 중합체를 포함하는 약제 조성물(Pharmaceutical compositions containing biodegradable polymers) 미국 특허 4,451 ,452 데이비그 등, 1984.5.29.등록을 포함한다. 전형적인 마이크로캡슐화된 약물 입자의 크기 범위는 하기 표에 나온 바와 같으며; 기술자는 목적하는 크기를 얻기 위하여 적절한 캡슐화 방법을 택할 수 있다. "Microencapsulated drug" means a drug particle encapsulated by a microencapsulated material. Non-limiting examples of such materials include proteins, polysaccharides, starches, waxes, fats, natural and synthetic polymers, and resins and / or combinations thereof. In a preferred example, the microencapsulated material is a synthetic polymer, preferably an ethyl acrylate-methyl methacrylate copolymer. Non-limiting examples of suitable methods for preparing microencapsulated drugs include fluidized bed coating, spray drying, spray chilling, spinning disk coating, stationary nozzle coextrusion, peptizing ( peptization, centrifugal head coextrusion, submerged nozzle coextrusion, pan coating, solvent evaporation, coacervation, simple and complex And phase separation, interfacial polymerization, in-situ polymerization, liposome technology and nanoencapsulation. One preferred example is a fluidized bed coating. Non-limiting examples of additional techniques and materials useful in the practice of the present invention include microencapsulation using emulsification / solvent evaporation: an overview of techniques and applications, Crit Rev Ther Drug Carrier Syst.) 1990; 7 (3): 235-59; Microcapsules for controlled oral drug delivery systems; US Patent 5,362,424 (1994.11.8. Registered); Microencapsulation process and products therefrom, US Pat. No. 5,407,609, Tais et al., 1995.4.18. Enrollment; Pharmaceutical compositions containing biodegradable polymers US Pat. No. 4,451,452 to David et al., 1984.5.29. The size ranges of typical microencapsulated drug particles are shown in the table below; The technician can choose an appropriate encapsulation method to obtain the desired size.
"비-마이크로캡슐화된 약물"은 실질적으로 마이크로캡슐화되지 않은 약물을 의미한다. 비-마이크로캡슐화된 약물은 새로운 제형의 한 층 또는 한 층 이상에 위치할 수 있다. 상기 하나 이상의 층에 존재하는 비-마이크로캡슐화된 약물의 일례에서, 비-마이크로캡슐화된 약물은 같거나 다른 농도로 각 층에 존재할 수 있다. 하나 이상(즉, 다른, 또는 혼합물)의 비-마이크로캡슐화된 약물이 새로운 제형내에 존재할 수 있다."Non-microencapsulated drug" means a drug that is not substantially microencapsulated. The non-microencapsulated drug can be located on one layer or more than one layer of the new formulation. In one example of a non-microencapsulated drug present in the one or more layers, the non-microencapsulated drug can be present in each layer at the same or different concentrations. One or more (ie other, or mixtures) of non-microencapsulated drugs may be present in the new formulation.
약물의 "방출의 속도" 또는 "방출 속도"는 단위 시간당 제형으로부터 방출되는 약물의 양, 예를 들어 시간당 방출되는 약물의 밀리그램(mg/hr)을 의미한다. 약물 제형에 대한 약물 방출 속도는 전형적으로 시험관내 약물 방출 속도, 즉 적절한 조건하에 적합한 유체 중에서 측정된 단위 시간당 제형으로부터 방출되는 약물의 양으로서 측정된다. 본 명세서에 기술된 실시예에 사용된 방출 속도 시험은 USP 타입 VII 배스 인덱서에 부착된 금속 코일 샘플 홀더에 놓인 제형에 대해서 37℃의 항온 수조에서 평형화된 약 50 mL의 산성화된 물(pH=3) 중에 침지하여 수행된다. 방출 속도 용액의 분취량을 크로마토그래피 시스템에 주입하여 시험 간격 동안 방출되는 약물의 양을 정량화한다."Rate of release" or "rate of release" of a drug means the amount of drug released from the formulation per unit time, for example, milligrams of drug released per hour (mg / hr). The rate of drug release for a drug formulation is typically measured as the rate of drug release in vitro, ie the amount of drug released from the formulation per unit time measured in a suitable fluid under appropriate conditions. The release rate test used in the examples described herein was performed in an approximately 50 mL of acidified water (pH = 3) equilibrated in a constant temperature water bath at 37 ° C for formulations placed in a metal coil sample holder attached to a USP Type VII bath indexer. By dipping). An aliquot of the release rate solution is injected into the chromatography system to quantify the amount of drug released during the test interval.
본 명세서에서 사용되는 바와 같이, 달리 명시되지 않는 한, "투여 후" 지정된 시간에 얻어진 약물 방출 속도는 적절한 용해 시험 수행 후 지정된 시간에 얻어진 시험관내 약물 방출 속도를 의미한다. 제형 내에서 지정된 퍼센트의 약물이 방출되는 시간을 "Tx" 값으로 해서 기준으로 할 수 있으며, 여기에서 "x"는 방출되는 약물 퍼센트를 나타낸다. 예를 들어, 제형으로부터 약물 방출을 평가하기 위해 통상적으로 사용되는 기준 측정치는 제형내 약물의 90%가 방출되는 시간이다. 이러한 측정치를 제형에 대한 "T90"이라고 한다. 편의상, 명확하기 위하여 약물 투여 시간을 0시간(t=0 시간)으로 보고, 투여 후 시간 단위는 예를 들면 t=30분 또는 t=2시간으로 한다. As used herein, unless otherwise specified, the drug release rate obtained at the designated time "after administration" means the in vitro drug release rate obtained at the designated time after performing the appropriate dissolution test. The time at which a specified percentage of drug is released in the formulation may be based on the "T x " value, where "x" represents the percentage of drug released. For example, a reference measure commonly used to assess drug release from a formulation is the time at which 90% of the drug in the formulation is released. This measurement is called "T90" for the formulation. For convenience, the drug administration time is reported as 0 hours (t = 0 hours), and the time unit after administration is, for example, t = 30 minutes or t = 2 hours.
"실질적으로 없다"는 제형, 층 또는 본 원소가 실질적으로 본 물질에 부존재함을 의미한다. 바람직한 일례에서, 제형, 층 또는 본 원소는 본 문질 중에 제형, 층 또는 본 원소 총 중량에 근거하여 약 5 wt%, 바람직하게는 약 2.5 wt%, 더욱 바람직하게는 1 wt%이하로 포함되어 있다. "Substantially free" means that the formulation, layer or present element is substantially absent from the present material. In a preferred embodiment, the formulation, layer or present element is included in the context in an amount of about 5 wt%, preferably about 2.5 wt%, more preferably 1 wt% or less, based on the total weight of the formulation, layer or the present element. .
"서방성"은 약물이 서방성 제형으로부터 약 12시간 또는 그 이상의 기간 정도 독성 레벨 이하의 치료 범위 내의 혈중(예, 혈장)농도로 유지되는 속도로 방출되는 것이다. “Sustained release” is the release of a drug from a sustained release formulation at a rate that maintains blood (eg, plasma) concentrations within a therapeutic range below the toxicity level for a period of about 12 hours or longer.
"서방성 제형"은 많은 시간 동안 약물을 실질적으로 지속적으로 방출하는 제형을 의미한다. 본 발명에 따른 서방성 제형은 1일 1회 용량에서 적어도 4시간 또는 그 이상의 T90 값을 나타내거나, 약 24시간 또는 그 이상의 T90 값을 나타낸다. 제형은 적어도 약 6시간, 바람직하게는 약 8시간 또는 그 이상 및, 특정 예에서는 약 12시간 또는 그 이상의 지속된 기간동안 약물을 연속적으로 방출한다."Sustained release dosage form" means a dosage form that releases the drug substantially continuously for many hours. Sustained release formulations according to the present invention exhibit a T90 value of at least 4 hours or more at a dose once daily, or a T90 value of about 24 hours or more. The formulation continuously releases the drug for a sustained period of at least about 6 hours, preferably about 8 hours or more, and in certain instances about 12 hours or more.
"0차 혈장 프로파일" 또는 "플랫 혈장 프로파일(flat plasma profile)"은 특정 시간 간격에 따른 환자의 혈장중의 특정 약물의 양이 실질적으로 고정되어 있거나 변동이 없는 것을 의미한다. 일반적으로, 0차 혈장 프로파일은 한 시간 간격에서 그 다음 시간 간격까지 약 10% 이하로 변할 것이다. "0th plasma profile" or "flat plasma profile" means that the amount of a particular drug in the patient's plasma over a certain time interval is substantially fixed or unchanged. In general, the zero-order plasma profile will vary by less than about 10% from one hour interval to the next.
"0차 방출 속도"는 실질적으로 일정한 방출 속도, 약물이 실질적으로 일정한 속도로 사용 환경에서 용액중에 용해되는 것을 의미한다. 더욱 자세하게는 약물의 방출 속도가 시간의 함수로서 약 30% 이하, 바람직하게는 약 20% 이하, 더욱 바람직하게는 약 10% 이하, 더욱 바람직하게는 약 5% 이하로 변하는 것을 의미하며, 여기에서 측정치는 축적 방출이 제형 중의 약물의 총 중량의 약 25 내지 약 75% 사이, 바람직하게는 약 25% 내지 약 90% 사이인 기간에 대해 측정된다.By "zero order release rate" is meant that the drug is dissolved in solution in the environment of use at a substantially constant release rate, at a substantially constant rate. More specifically, the rate of release of the drug varies as a function of time up to about 30%, preferably up to about 20%, more preferably up to about 10%, more preferably up to about 5%, wherein The measurement is measured for a period in which the cumulative release is between about 25 to about 75%, preferably between about 25% and about 90% of the total weight of the drug in the formulation.
"실질적으로 봉합된"은 제형, 층 또는 본 원소가 실질적으로 본 물질을 인글로브(englobe), 코팅하거나 덮는 것(cover)을 의미한다. 바람직한 일례에서, 제형, 층, 또는 본 원소는 본 물질의 총 표면적에 근거하여 약 30% 이상, 바람직하게는 약 50% 이상, 더욱 바람직하게는 약 75% 이상, 더욱 바람직하게는 약 100%를 봉합한다. "Substantially sealed" means that the formulation, layer, or element is substantially in the globe, coating or covering the material. In a preferred embodiment, the formulation, layer, or element is based on the total surface area of the present material at least about 30%, preferably at least about 50%, more preferably at least about 75%, more preferably at least about 100% Suture.
구체예의 설명Description of Embodiment
도 1은 본 발명에 따른 서방성 제형 100을 나타낸다. 서방성 제형 100중에는 지연층 102, 제2층 104, 마이크로캡슐화된 약물 110, 및 비-마이크로캡슐화된 약물 112가 포함된다. 지연층 102는 제2층 104에 인접하여 위치한다. 지연층 102는 중합체 매트릭스 120 및 마이크로캡슐화된 약물 112를 포함한다. 실험에서, 지연층 102는 지연층 104 및 제2층 104의 접촉 부분으로 정의되는 계면으로부터 비-마이크로캡슐화된 약물 112의 방출을 지연시켜 서방성 제형 100으로부터의 약물 방출을 지연시키는 작용을 한다. 이는 지연층의 부식 및 지연층을 통한 약물의 확산의 조합을 통해 일어날 수 있다. 마이크로캡슐화된 약물 110의 방출은 도한 마이크로캡슐화에 의해 지연된다. 일반적으로(이 메카니즘은 본 발명에 다른 다양한 예의 실험으로 설명할 수 있음을 의미), 마이크로캡슐화된 약물 110이 GI 액과 같은 미디아와 접촉하게 되었을 때(제형 100의 표면, 중합체 매트릭스 120의 부식 또는 중합체 매트릭스 120을 통한 확산의 수단으로), 마이크로캡슐화된 물질은 코팅층에 있는 기공을 떠나 조절된 양상으로 서서히 용해되며 이 기공을 통해 약물이 방출된다. 지연층의 효과에 약물의 마이크로캡슐화의 효과가 더해져 오름차 방출속도가 나타나게 된다. 1 shows a
도 2는 본 발명에 따른 서방성 제형 200을 나타낸다. 서방성 제형 200은 지연층 202, 제2층 204, 제2층 206, 마이크로캡슐화된 약물 210, 비-마이크로캡슐화된 약물 212, 1차 중합체 매트릭스 220, 2차 중합체 매트릭스 222, 및 3차 중합체 매트릭스 224를 포함한다. 지연층 202는 제2층 104에 인접하여 위치한다. 지연층 202는 중합체 매트릭스 220 및 마이크로캡슐화된 약물 210을 포함한다. 제2층 204는 중합체 매트릭스 222 및 비-마이크로캡슐화된 약물 212를 포함한다. 제2층 206은 지연층 202와 반대로 제형 200의 부분 위에 있는 제2층 204에 인접하여 위치한다. 제2 지연층 206은 중합체 매트릭스 224 및 마이크로캡슐화된 약물 210을 포함한다. 2 shows a
실험에서, 제형 200을 그들이 필요한 환자에게 투여하였을 때, 지연층 202 및 제2층 206은 지연층 202 및 제2 지연층 206과 접촉하는 제2층 204의 부분으로 정의되는 계면으로부터 비-마이크로캡슐화된 약물 212의 방출이 지연시켜 제형 200으로부터의 약물 방출이 지연되도록 작용한다. 이는 지연층의 부식에 지연층을 통한 약물 확산이 더해져 일어날 수 있다. 마이크로캡슐화된 약물 210의 방출은 또한 마이크로캡슐화 효과에 의해 지연된다. 제형 200은 자연상태에서 다공성인 중합체 매트릭스 제형을 포함한다. 중합체 매트릭스가 물 또는 수성 위장관액에 접촉할 때, 중합체 매트릭스중의 중합체는 물 또는 용액을 흡수하여 팽창하거나 수화한다. 이 과정은 중합체 사슬의 이완을 야기하고, 그 결과 사슬이 풀리고, 사슬 사이의 분리 거리가 증가하여 약물이 확산된다. 상기 언급된 바와 같이, 부식, 확산, 및 중합체 매트릭스의 팽창과 마이크로캡슐 밖으로의 용해의 조합은 약물 방출을 조절하는 이러한 시스템을 통한 다양한 방법이 된다. 중합체 매트릭스 및 마이크로캡슐화된 물질의 방출력의 밸런스를 맞춰, 오름차 방출 프로파일을 얻을 수 있다. In the experiment, when
여기에 제형 200으로 소개된 새로운 제형(그러나 다른 제형도 또한 가능)을 통상의 중합체 매트릭스(예를 들면, 비교예 1)와 비교해보면, 방출 프로파일에서 세 가지 구별되는 점이 있는데: (a) 초기 즉시방출이 감소한다. 특정 매카니즘에 의해 제한되는 것은 아니지만, 이러한 효과는 바깥층에 존재하는 마이크로캡슐화된 약물 및 이 바깥층의 조합에 의한 기여일 수 있고(다량의 낮은 친수성의 중합체는 지연층에 더욱 소수성인 성질을 주고, 이는 초기 즉시 팽창 및 약물 방출을 막을 수 있다); (b) "오름차 프로파일"을 특징으로 하는 프로파일에서 피크가 존재한다. 이 효과는 아마도, 시간에 따라 비-마이크로캡슐화된 약물의 방출과 부식 및 확산 매카니즘에 의한 중합체 매트릭스를 통한 마이크로캡슐화된 약물의 조합에 의해 얻어지게 되며; 및 (c) 프로파일의 종말점에서 방출이 끝난다. 이 효과는 중합체 확산 및 부식 뿐만 아니라 마이크로캡슐화된 약물의 방출에 기인할 것이다.When comparing the new formulation introduced here as Formulation 200 (but other formulations are also possible) with a conventional polymer matrix (eg, Comparative Example 1), there are three distinctions in the release profile: (a) early immediate Emission is reduced. While not limited by any particular mechanism, this effect may be a contribution by the combination of the microencapsulated drug present in the outer layer and the outer layer (a large amount of low hydrophilic polymer gives the retardation layer more hydrophobic properties, which Prevent initial immediate swelling and drug release); (b) There is a peak in the profile characterized by the "ascending profile". This effect is probably achieved by the combination of the release of the non-microencapsulated drug with time and the microencapsulated drug through the polymer matrix by the corrosion and diffusion mechanisms; And (c) the release ends at the end of the profile. This effect will be due to polymer diffusion and corrosion as well as release of the microencapsulated drug.
도 3은 본 발명에 따른 서방성 제형 300을 나타낸다. 서방성 제형 300은 지연층 302, 2번째 층 204, 마이크로캡슐화된 약물 310, 비-마이크로캡슐화된 약물 312, 1차 중합체 매트릭스 320, 및 2차 중합체 매트릭스 322를 포함한다. 지연층 302는 실질적으로 2번째 층 304를 둘러싼다. 지연층 302는 중합체 매트릭스 320 및 마이크로캡슐화된 약물 310을 포함한다. 제2층 304는 중합체 매트릭스 322 및 비-마이크로캡슐화된 약물 312를 포함한다. 실험에서, 제형 300이 이들이 필요한 환자에게 투여되었을 때, 지연층 302는 제2층 306에서 비-마이크로캡슐화된 약물 312의 방출이 지연되어 제형 300으로부터 약물의 방출을 지연시킨다. 이는 지연층의 부식 및 지연층을 통한 약물의 확산의 조합을 통해 일어날 수 있다. 제형 300에 적용되는 방출 매카니즘은 제형 200에서 언급된 바 있다. 3 shows a
도 4는 본 발명에 따른 서방성 제형 400을 나타낸다. 서방성 제형 400에는 지연층 402, 제2층 404, 제2층 406, 마이크로캡슐화된 약물 410, 비-마이크로캡슐화된 약물 412, 1차 중합체 매트릭스 420, 2차 중합체 매트릭스 422, 및 3차 중합체 매트릭스 424를 포함한다. 지연층 402는 제2층 404에 인접하여 위치한다. 지연층 402는 중합체 매트릭스 420 및 마이크로캡슐화된 약물 410을 포함한다. 제2층 404는 중합체 매트릭스 422, 마이크로캡슐화된 약물 410, 및 비-마이크로캡슐화된 약물 412를 포함한다. 제2 지연층 406은 지연층 402의 반대편의 제형 400의 부분위에 있는 제2층 404에 인접하여 위치한다. 제2 지연층 406은 중합체 매트릭스 424 및 마이크로캡슐화된 약물 410을 포함한다. 실험에서, 제형 400을 이를 필요로 하는 환자에게 투여하였을 때, 지연층 402 및 제2 지연층 406은 지연층 402 및 제2 지연층 406과 접촉하는 제2층 404의 부분으로 저의되는 계면으로부터 비-마이크로캡슐화된 약물 412가 방출되는 것을 지연시켜 제형 400으로부터 약물이 방출되는 것을 지연시키는 작용을 한다. 이는 지연층을 통한 약물의 확산 및 지연층의 부식의 조합으로 인해 일어날 것이다. 제형 400에 적용되는 방출 매카니즘은 제형 200에서 설명한 바 있다.4 shows a
도 5는 본 발명에 따른 서방성 제형 500을 나타낸다. 서방성 제형 500에는 지연층 502, 제2층 504, 바깥 지연층 508, 마이크로캡슐화된 약물 510, 비-마이크로캡슐화된 약물 512, 1차 중합체 매트릭스 520, 2차 중합체 매트릭스 522, 및 3차 중합체 매트릭스 524가 포함된다. 바깥 지연층 508은 실질적으로 지연층 502를 둘러싼다. 지연층 502는 1차 중합체 520 및 마이크로캡슐화된 약물 510을 포함한다. 실험에서, 제형 500을 이를 필요로 하는 환자에게 투여하였을 때, 지연층 502는 제2층 504로부터 비-마이크로캡슐화된 약물 512가 지연방출되어 제형 500으로부터의 약물이 지연되어 방출되도록 작용한다. 이는 지연층의 부식 및 지연층을 통한 약물 확산의 조합을 통해 발생할 수 있다. 바깥 지연층 508은 또한 방출을 지연시키고, 임의의 초기 즉시방출을 감소시키거나 초기 조절하의 제형 500으로부터의 방출을 감소시키는 것을 보조한다. 제형 500에 적용되는 방출 매카니즘은 제형 200에 설명된 바 있다. 5 shows a
도 6은 본 발명에 따른 서방성 제형 600을 나타낸다. 서방성 제형 600에는 지연층 602, 제2 지연층 606, 3차 지연층 608, 4차 지연층 609, 마이크로캡슐화된 약물 610, 비-마이크로캡슐화된 약물 612, 1차 중합체 매트릭스 620, 2차 중합체 매트릭스 622, 및 3차 중합체 매트릭스 624, 4차 중합체 매트릭스 626, 5차 중합체 매트릭스 628이 포함된다. 지연층 602는 3차 지연층 608에 인접하여 위치한다. 지연층 602는 1차 중합체 매트릭스 620 및 마이크로캡슐화된 약물 610을 포함한다. 3차 지연층 608은 제2층 604에 인접하여 위치한다. 3차 지연층 608은 중합체 매트릭스 622를 포함한다. 제2층 604는 3차 중합체 매트릭스 624 및 비-마이크로캡슐화된 약물 612를 포함한다. 4차 지연층 609는 지연층 602 반대편 제형 600의 부분위에 있는 제2층 604에 인접하여 위치한다. 4차 지연층 606은 4차 중합체 매트릭스 626을 포함한다. 제2 지연층 606은 제2층 604 반대편 4차 지연층 609의 측면위에 있는 4차 지연층 609에 인접하여 위치한다. 제2 지연층 606은 5차 중합체 매트릭스 628 및 마이크로캡슐화된 약물 610을 포함한다. 실험에서, 제형 600이 이들을 필요로 하는 환자에게 투여되었을 때, 지연층 602, 제2 지연층 606, 3차 지연층 608, 및 4차 지연층 609는 비-마이크로캡슐화된 약물 612의 방출을 지연시켜 제형 600으로부터 약물이 방출되는 것을 지연시키는 작용을 한다. 이는 지연층을 통한 약물의 확산 및 지연층의 부식의 조합을 통해 발생할 수 있다. 특히, 3차 지연층 608 및 4차 지연층 609의 조성물 및 두께는 제형 600으로부터 비-마이크로캡슐화된 약물 612가 초기 방출 또는 즉시방출을 감소시키기 위하여 선택될 수 있다. 제형 600에 적용되는 방출 매카니즘은 상기 제형 200에서 설명된 바 있다. 6 shows a
새로운 제형은 이 기술분야에 알려진 통상의 기술을 사용하여 만들 수 있다. 상기 기술의 비한정적 예로 미국 특허 5,980,942 (Katzhendler 등)이 있다. 본 발명에 따른 제형을 제조하는 것과 관련된 부가 정보는 특히 Development of a Controlled Release Matrix Tablet Containing a Water-Soluble Drug Utilizing Hypromellose and Ethylcellulose. Tina Dasbach, Pushpa Inbasekaran, and Karen Balwinski The Dow Chemical Company, Midland, Ml 48674; The Effect of Process Conditions on Various Sustained Release Formulations During Wet Granulation. Pushpa Inbasekaran and Karen Balwinski.The Dow Chemical Company, Midland, Ml 48674; Direct Compression of Sustained-Release Hydrophilic Matrix Tablets Containing Hypromellose and MCC: Effects of a Lubricant T. D. Cabelka Technical Service and Development for METHOCEL Cellulose Ethers Larkin Laboratory, The Dow Chemical Company, Midland, Ml 48674 USA; Lab-Scale to Full Production Scale Evaluation of a Controlled-Release Formulation Based on Hypromellose and Manufactured Using Roll Compaction Technology Paul Sheskeyi, Kerry Pacholkel , Gary Sackett2, and Larry Maher, 1 The Dow Chemical Company Larkin Laboratory Midland, Ml 48674. 2 The Vector Corporation Marion, IA 52302; The Utility of Hydroxypropyl Methylcellulose as a Porosity Modifier in an Ethylcellulose Compression Coating Douglas K. Pollock and Karen M. Balwinski Presented at the 27th International Symposium on Controlled Release of Bioactive Materials Paris, France, July 7-13, 2000 The Dow Chemical Company Larkin Laboratory, Midland, Ml 48674 USA에서 볼 수 있다. New formulations can be made using conventional techniques known in the art. Non-limiting examples of such techniques are US Pat. No. 5,980,942 to Katzhendler et al. Additional information relating to the preparation of the formulations according to the invention can be found in particular in Development of a Controlled Release Matrix Tablet Containing a Water-Soluble Drug Utilizing Hypromellose and Ethylcellulose. Tina Dasbach, Pushpa Inbasekaran, and Karen Balwinski The Dow Chemical Company, Midland, Ml 48674; The Effect of Process Conditions on Various Sustained Release Formulations During Wet Granulation. Pushpa Inbasekaran and Karen Balwinski. The Dow Chemical Company, Midland, Ml 48674; Direct Compression of Sustained-Release Hydrophilic Matrix Tablets Containing Hypromellose and MCC: Effects of a Lubricant T. D. Cabelka Technical Service and Development for METHOCEL Cellulose Ethers Larkin Laboratory, The Dow Chemical Company, Midland, Ml 48674 USA; Lab-Scale to Full Production Scale Evaluation of a Controlled-Release Formulation Based on Hypromellose and Manufactured Using Roll Compaction Technology Paul Sheskeyi, Kerry Pacholkel, Gary Sackett2, and Larry Maher, 1 The Dow Chemical Company Larkin Laboratory Midland, Ml 48674. 2 The Vector Corporation Marion, IA 52302; The Utility of Hydroxypropyl Methylcellulose as a Porosity Modifier in an Ethylcellulose Compression Coating Douglas K. Pollock and Karen M. Balwinski Presented at the 27th International Symposium on Controlled Release of Bioactive Materials Paris, France, July 7-13, 2000 The Dow Chemical Company Larkin Laboratory, Midland, Ml 48674 USA.
본 발명의 제형에 도입된 약물의 양은 약물의 종류, 치료 적응증 및 예를 들면 매 12시간, 매 24시간 등의 목적하는 투여기간에 따라 다양하다. 투여되는 목적약물의 양에 따라 하나 이상의 제형이 투여될 수 있다. The amount of drug introduced into the formulation of the present invention will vary depending on the type of drug, the indication of treatment and the desired duration of administration, for example every 12 hours, every 24 hours, and the like. One or more formulations may be administered depending on the amount of drug of interest administered.
연장된 기간동안 서방성 및 오름차 방출속도를 갖는 제형의 사용으로 인해 향상시킬 수 있는 임상케이스 및 약물 치료는 다양하게 존재한다. 일례로 본 명세서에 개시된 제형에는 CNS-작용 약물 및 심혈관계 작용 약물이 포함된다. 본 발명을 다른 많은 타입의 약물 및 약물 치료에 적용할 수 있다는 것을 이 기술분야의 기술자에게 자명할 것이다. 적절한 타입의 약물의 비한정적 예로는 항-감염제, 진통제, 마취제, 관절염치료제, 항천식제, 경련방지제(anticonvulsant), 항우울제, 항당뇨제, 지사제, 항히스타민제, 항염증제, 항편두통제, 항종양제, 항파킨슨씨제, 항소양제, 항정신병제, 해열제, 진경제(antispasmodics), 항콜린제, 교감신경흥분제(sympathomimetics), 칼슘 채널 차단제, 베타 차단제, 항부정맥제(antiarrythmics), 항고혈압제, ACE 저해제, 이뇨제, 혈관확장제, 충혈완화제, 호르몬, 수면제(hypnotics), 면역억제제, 부교감신경억제제 (parasympathomimetics), 프로스타글란딘, 단백질, 펩티드, 진정제(sedatives), 정신안정제(tranquilizers)를 포함한다. There are a variety of clinical cases and medications that can be improved due to the use of formulations with sustained release and ascending release rates for extended periods of time. In one example, formulations disclosed herein include CNS-acting drugs and cardiovascular acting drugs. It will be apparent to those skilled in the art that the present invention can be applied to many other types of drugs and drug treatments. Non-limiting examples of suitable types of drugs include anti-infective agents, analgesics, anesthetics, arthritis medications, anti-asthma medications, anticonvulsants, antidepressants, antidiabetics, antidiabetics, antihistamines, anti-inflammatory drugs, anti-migraine drugs, anti-tumor drugs , Antiparkinsonism, antipruritic, antipsychotic, antipyretic, antispasmodics, anticholinergic, sympathomimetics, calcium channel blockers, beta blockers, antiarrythmics, antihypertensives, ACE inhibitors, diuretics , Vasodilators, decongestants, hormones, hypnotics, immunosuppressants, parasympathomimetics, prostaglandins, proteins, peptides, sedatives, tranquilizers.
본 발명에 따른 제형은 비한정적 예로 CNS 및 심혈관계 적응증을 포함하는 다양한 적응증의 치료에 투여될 수 있다. The formulations according to the invention can be administered in the treatment of various indications including but not limited to the CNS and cardiovascular indications.
본 발명에 개시된 하기 실시예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위를 하등 제한하는 것으로 간주해서는 안되며, 이들 실시예 및 기타 그와 동등한 것들은 본 명세서에 개시된 설명, 도면 및 첨부한 청구의 범위를 감안해서 당업계에서 통상의 지식을 가진 자에게는 명백하게 될 것이다. The following examples disclosed herein are intended to illustrate the invention and should not be considered as limiting the scope of the invention in any way, and these examples and other equivalents thereof are set forth in the description, drawings and appended claims disclosed herein. It will be apparent to those of ordinary skill in the art in view of the scope.
도 1은 본 발명에 따른 제형을 나타낸다. 1 shows a formulation according to the invention.
도 2는 본 발명에 따른 제형을 나타낸다.2 shows a formulation according to the invention.
도 3은 본 발명에 따른 제형을 나타낸다.3 shows a formulation according to the invention.
도 4는 본 발명에 따른 제형을 나타낸다.4 shows a formulation according to the invention.
도 5는 본 발명에 따른 제형을 나타낸다.5 shows a formulation according to the invention.
도 6은 본 발명에 따른 제형을 나타낸다.6 shows a formulation according to the invention.
도 7은 방출 속도 데이타를 나타낸다. 7 shows release rate data.
도 8은 방출 속도 데이타를 나타낸다. 8 shows release rate data.
도 9는 본 발명에 따른 제형을 나타낸다.9 shows a formulation according to the invention.
도 10은 방출 속도 데이타를 나타낸다. 10 shows release rate data.
도 11은 방출 속도 데이타를 나타낸다. 11 shows release rate data.
도 12는 제형의 레이아웃을 나타낸다.12 shows the layout of the formulation.
도 13은 방출 속도 데이타를 나타낸다.13 shows release rate data.
실시예 1Example 1
라벨 청구범위의 약 5%가 제형의 지연층에 마이크로캡슐화된 약물로 제형중 에 존재하고 라벨 청구범위의 약 95%는 제2층에 프리 약물로 존재한다. 이러한 배치는 오름차 방출속도를 제공하기 위한 것이다. About 5% of the label claims are present in the formulation as drugs microencapsulated in the delayed layer of the formulation and about 95% of the label claims are present as free drugs in the second layer. This arrangement is to provide ascending release rates.
토피라메이트의 마이크로캡슐화: 토피라메이트 50 g을 칭량하여 비이커에 옮겼다. 콜리코트 30DEMM(Kollicoat 30DEMM) 6 g을 토피라메이트에 적가하고 스파툴라로 5분동안 혼합하였다. 습윤 매스를 8 메쉬 스크린에 통과시키고 72시간동안 에어 드라이를 시켰다. 건조된 매스를 12 메쉬 스크린에 통과시켰다. 과립을 트래이 위에 놓고 6 g의 콜리돈 30DEMM을 과립위에 분무하고 28 ℃, 주위습도 조건에서 오븐에 방치하였다. 코팅 과정은 두번 반복하여 행하였고, 각 과정에서 약 6 g의 콜리돈 30DEMM을 첨가하였다. 세번째 코팅 후, 과립을 오븐에 하룻밤 남겨놓고, 건조 과립을 8 메쉬 스크린에 통과시켰다.Microencapsulation of Topiramate: 50 g of Topiramate were weighed and transferred to a beaker. 6 g of Kollicoat 30DEMM was added dropwise to Topiramate and mixed for 5 minutes with spatula. The wet mass was passed through an 8 mesh screen and air dried for 72 hours. The dried mass was passed through a 12 mesh screen. The granules were placed on a tray and 6 g of collidone 30DEMM was sprayed onto the granules and left in an oven at 28 ° C. and ambient humidity conditions. The coating process was repeated twice, and about 6 g of collidone 30DEMM was added in each process. After the third coating, the granules were left in the oven overnight and the dry granules passed through an 8 mesh screen.
지연층의 제조: 230.8 mg 의 상기 마이크로캡슐화된 토피라메이트를 1.3 g의 HPMC K100 M Prem CR 및 1.3 g의 에틸 셀룰로즈와 혼합하였다. 물질을 롤러 믹서(U.S. Stoneware Jar Mill (Model 764 AVM))중에서 30분동안 혼합하였다.Preparation of retardation layer: 230.8 mg of the microencapsulated topiramate was mixed with 1.3 g of HPMC K100 M Prem CR and 1.3 g of ethyl cellulose. The material was mixed for 30 minutes in a roller mixer (U.S. Stoneware Jar Mill (Model 764 AVM)).
제2층의 제조: 2.8 g의 토피라메이트를 1.9 g의 HPMC K15M Prem CR 및 1.7 g의 에틸 셀룰로즈와 혼합하고 롤러 믹서((U.S. Stoneware Jar Mill (Model 764 AVM)))로 30분간 혼합하였다. 3.4 g의 PEG 3350 및 30 mg의 블랙 산화제2철을 가하고 롤러밀로 20분간 혼합하였다. 30 mg의 마그네슘 스테아레이트를 가하고 30초간 혼합하였다.Preparation of Second Layer: 2.8 g of Topiramate was mixed with 1.9 g of HPMC K15M Prem CR and 1.7 g of ethyl cellulose and mixed for 30 minutes with a roller mixer (U.S. Stoneware Jar Mill (Model 764 AVM)). 3.4 g PEG 3350 and 30 mg black ferric oxide were added and mixed for 20 minutes with a roller mill. 30 mg magnesium stearate was added and mixed for 30 seconds.
정제의 압축: 32.5 mg의 지연층 조성물을 칭량하고, 3/8" 원오목형 펀치세트의 주형공간에 넣었다. 지연층을 가볍게 다졌다. 335 mg의 제2층 조성물을 다져서 굳힌 지연층에 첨가하고 가볍게 다져주었다. 32.5 mg의 지연층 조성물을 첨가한 후 정제를 카버 프레스(Carver press)중에서 2 톤의 압축력을 주어 압축하였다. Compression of tablets: 32.5 mg of the delay layer composition was weighed and placed in the mold space of a 3/8 "conical punch set. The delay layer was lightly chopped. 335 mg of the second layer composition was chopped and added to the hardened delay layer. After the addition of 32.5 mg of the delayed layer composition, the tablets were compressed in a Carver press with 2 tons of compressive force.
약물 방출의 측정: USP 타입 2 기구를 사용하여 물 중에서 압축된 정제의 약물 방출을 분석하였다. 결과를 도 7에 나타냈다. Determination of Drug Release: The drug release of the compressed tablets in water was analyzed using a
실시예 2:Example 2:
라벨 청구범위의 약 5%가 제형의 지연층에 마이크로캡슐화된 약물로 제형중에 존재하고 라벨 청구범위의 약 95%는 제2층 2에 비-마이크로캡슐화된 약물 42.5% 및 마이크로캡슐화된 약물 42.5%로 존재한다. 이러한 배치는 오름차 방출속도를 제공하기 위한 것이다. About 5% of the label claims are present in the formulation as drugs microencapsulated in the delayed layer of the formulation and about 95% of the label claims are 42.5% non-microencapsulated drug and 42.5% microencapsulated drug in the
마이크로캡슐화된 토피라메이트는 실시예 1에 개시된 바와 같이 제조한다. 지연층 조성물을 실시예 1에 개시된 바대로 제조하였다. Microencapsulated topiramate is prepared as disclosed in Example 1. The retardation layer composition was prepared as disclosed in Example 1.
제2층의 제조: 1.4 g의 토피라메이트를 1.4 g의 마이크로캡슐화된 토피라메이트(실시예 1에 개시된 바대로 제조), 1.9 g의 HPMC K15M Prem CR 및 1.7 g의 에틸 셀룰로즈와 혼합한 후 롤러믹스(U.S. Stoneware Jar Mill (Model 764 AVM)) 중에서 30분동안 혼합하였다. 3.4 g의 PEG 3350 및 30 mg의 블랙 산화 제2철을 첨가하고 롤러밀에서 20분동안 혼합하였다. 30 mg의 마그네슘 스테아레이트를 첨가하고 30초동안 혼합하였다. Preparation of the second layer: 1.4 g of topiramate was mixed with 1.4 g of microencapsulated topiramate (prepared as described in Example 1), 1.9 g of HPMC K15M Prem CR and 1.7 g of ethyl cellulose followed by a rollermix (US Stoneware Jar Mill (Model 764 AVM)) for 30 minutes. 3.4 g PEG 3350 and 30 mg black ferric oxide were added and mixed on a roller mill for 20 minutes. 30 mg magnesium stearate was added and mixed for 30 seconds.
실시예 1의 지연 조성물 및 앞에서 제조된 제2층 조성물을 사용하여 실시예 1의 방법에 따라 압축된 정제를 제조하였다.A compressed tablet was prepared according to the method of Example 1 using the delay composition of Example 1 and the second layer composition prepared above.
결과를 도 8에 나타냈다. The results are shown in FIG.
실시예 3:Example 3:
라벨 청구범위의 67%가 내부 코어중에 마이크로캡슐화된 약물로 존재하고 라벨 청구범위의 33%가 내부 층중에 마이크로캡슐화된 약물로 존재한다. 바깥 끝 캡에는 약물이 없다. 이러한 배치가 오름차 방출 프로파일을 제공한다.67% of the label claims exist as microencapsulated drugs in the inner core and 33% of the label claims exist as microencapsulated drugs in the inner layer. There is no drug in the outer end cap. This arrangement provides an ascending release profile.
1 단계: 팔리페리돈의 마이크로캡슐화Step 1: Microencapsulation of Paliperidone
배취 #1Batch # 1
팔리페리돈 1 gm을 칭량하여 비이커에 넣고 HPMC K100 Prem 2 gm을 넣었다. 에탄올/콜리코트 EMM 3OD (83/17 wt/wt) 혼합물 약 1.4 gm을 혼합물에 첨가하여 과립화하였다.1 gm of paliperidone was weighed and placed in a beaker and 2 gm of HPMC K100 Prem. About 1.4 gm of ethanol / colicoat EMM 3OD (83/17 wt / wt) mixture was added to the mixture to granulate.
배취 #2
팔리페리돈 6 gm을 칭량하여 비이커에 넣고 HPMC K100 Prem 2 gm을 넣었다. 에탄올/콜리코트 EMM 3OD (75/25 wt/wt) 혼합물 약 1.8 gm을 혼합물을 과립화하기 위하여 첨가하였다.6 gm of paliperidone was weighed and placed in a beaker with 2 gm of HPMC K100 Prem. About 1.8 gm of ethanol / colicoat EMM 3OD (75/25 wt / wt) mixture was added to granulate the mixture.
배취 #3Batch # 3
콜리코트 EMM 30D 약 4.8 gm을 혼합물을 과립화하기 위하여 배취 #2의 1.35gm에 첨가하였다.Approximately 4.8 gm of Colicott EMM 30D was added to 1.35 gm of
2 단계: 바깥층, 내부 약물층 및 내부 코어의 제조Step 2: Preparation of the Outer Layer, Inner Drug Layer, and Inner Core
3 단계: 코어 압축Step 3: core compression
내부 코어층 30 mg을 칭량하여 5/32" 원오목형 펀치세트의 주형공간에 넣었다. 1 톤의 압축력을 카버 프레스에 적용하여 단일층 내부 코어를 제조하였다.30 mg of the inner core layer was weighed and placed in the mold space of a 5/32 "conical punch set. A single layer inner core was prepared by applying a compression force of 1 ton to a Carver press.
바깥층 80 mg을 칭량한 후 원오목형 펀치세트의 3/8" 주형공간에 첨가하였다. 층을 가볍게 다져주었다. 내부층 329 mg을 칭량하였다. 내부 약물층의 일부를 다져진 바깥층에 첨가하고 내부 압축 코어를 주형공간 중심에 위치시켰다. 잔여 내부 약물층 과립을 주형공간에 첨가하고 가볍게 다져주었다. 바깥층 80 mg을 칭량하여 주형공간에 첨가한 후, 캡슐화된 내부 코어가 있는 삼중층 코어를 카버 프레스로 2 톤의 압축력을 주어 압축하였다. 코어 구조를 도 9에 도시하였다.80 mg of the outer layer was weighed and then added to the 3/8 "mold space of the conical punch set. The layer was lightly chopped. The inner layer 329 mg was weighed. A portion of the inner drug layer was added to the chopped outer layer and compressed internally The core was placed in the center of the mold space The remaining inner drug layer granules were added to the mold space and lightly chopped The outer layer 80 mg was weighed and added to the mold space, then the triple layer core with the encapsulated inner core was transferred to a Carver press. Compression was given with a compression force of 2 tons The core structure is shown in FIG.
4 단계 : 약물 방출의 측정Step 4: measuring drug release
3 단계에서 제조한 압축 코어를 USP 타입 II 기구(UV 분석)를 사용하여 AGF중에서의 약물 방출을 측정하였다. 결과를 도 10에 도시하였다.Compression cores prepared in step 3 were measured for drug release in AGF using the USP Type II instrument (UV analysis). The results are shown in FIG.
실시예 4Example 4
라벨 청구범위의 67%가 내부 코어중에 마이크로캡슐화된 약물로 존재하고 라벨 청구범위의 33%가 내부층 중에 마이크로캡슐화된 약물로 존재한다. 바깥 끝 캡은 약물-프리이다. 이러한 배치로 오름차 방출 프로파일이 나타난다.67% of the label claims exist as microencapsulated drugs in the inner core and 33% of the label claims exist as microencapsulated drugs in the inner layer. The outer end cap is drug-free. This arrangement results in an ascending emission profile.
1 단계: 리스페리돈의 마이크로캡슐화Step 1: Microencapsulation of Risperidone
배취 #1Batch # 1
리스페리돈 1 g을 칭량하여 비이커에 넣고 HPMC K100 Prem 2 g을 넣었다. 에탄올/콜리코트 EMM 3OD (83/17 wt/wt) 혼합물 약 1.4 g을 혼합물을 과립화하기 위하여 첨가하였다.1 g of risperidone was weighed into a beaker and 2 g of HPMC K100 Prem was added. About 1.4 g of an ethanol / colicoat EMM 3OD (83/17 wt / wt) mixture was added to granulate the mixture.
배취 #2
리스페리돈 6 g을 칭량하여 비이커에 넣고 HPMC K100 Prem 2 g을 넣었다. 에탄올/콜리코트 EMM 3OD (75/25 wt/wt) 혼합물 약 1.8 g을 혼합물을 과립화하기 위하여 첨가하였다.6 g of risperidone was weighed into a beaker and 2 g of HPMC K100 Prem was added. Approximately 1.8 g of ethanol / colicoat EMM 3OD (75/25 wt / wt) mixture was added to granulate the mixture.
배취 #3Batch # 3
콜리코트 EMM 30D 약 4.8 g을 혼합물을 과립화하기 위하여 배취 #2의 1.35g에 첨가하였다.Approximately 4.8 g of Colicott EMM 30D was added to 1.35 g of
2 단계: 바깥층, 내부 약물층 및 내부 코어 제조Step 2: manufacture the outer layer, inner drug layer and inner core
3 단계: 코어 압축Step 3: core compression
압축된 정제를 실시예 3에서 제조된 코어층 조성물을 사용하여 실시예 3의 과정에 따라 제조하였다.Compressed tablets were prepared according to the procedure of Example 3 using the core layer composition prepared in Example 3.
비교예 1:Comparative Example 1:
약물의 라벨 청구범위의 100%가 매트릭스 코어에 존재한다. 이러한 배치는 후술하는 바와 같이 대체로 0차 방출속도를 나타내었다. 100% of the label claims of the drug are in the matrix core. This arrangement generally exhibited zero order release rates as described below.
토피라메이트 28.6 g을 21.5 g의 HPMC K100M Prem 및 14.3 g의 에틸 셀룰로즈 및 35.14 g의 폴리에테일렌(polyetheylene) 글리콜 3350과 혼합하였다. 구성성분들을 롤러믹서((U.S. Stoneware Jar Mill (Model 764 AVM))로 30분동안 혼합하였다. 0.5 g의 Mg 스테아레이트를 첨가하고 30초동안 혼합하였다. 28.6 g of topiramate were mixed with 21.5 g of HPMC K100M Prem and 14.3 g of ethyl cellulose and 35.14 g of polyetheylene glycol 3350. The ingredients were mixed for 30 minutes with a roller mixer (U.S. Stoneware Jar Mill (Model 764 AVM)) 0.5 g of Mg stearate was added and mixed for 30 seconds.
상기 블렌드 350 mg을 카버 프레스의 3/8" 툴링세트(tooling set)를 사용하여 2 톤의 힘으로 압축하였다. The blend 350 mg was compressed with a force of 2 tons using a 3/8 "tooling set from Carver Press.
압축된 정제에 대해 USP 타입 2 기구를 사용하여 물 중에서의 약물 방출을 측정하였다. Drug release in water was measured using a
그 결과를 도 11에 도시하였다. The results are shown in FIG.
비교예 2:Comparative Example 2:
라벨 청구범위의 100%가 내부층에 마이크로캡슐화된 약물로 존재한다. 바깥끝 캡은 약물-프리이다. 이러한 배치는 0차 방출 프로파일을 제공한다. 100% of the label claims are present as drugs encapsulated in the inner layer. The outer cap is drug-free. This arrangement provides a zero order emission profile.
1 단계: 바깥층 및 내부 약물층의 제조Step 1: Preparation of the Outer Layer and the Inner Drug Layer
2 단계 : 코어 압축Step 2: compress the core
바깥층을 75 mg을 칭량하여 3/8" 원오목형 펀치세트의 주형공간에 첨가하였다. 상기 층을 가볍게 다져주었다. 내부층 300 mg을 칭량하여 다져진 바깥층에 첨가하였다. 과립을 가볍게 다져주었다. 바깥층을 75 mg 칭량하여 주형공간에 첨가하고 카버 프레스로 3톤의 압축력을 주어 삼중층 코어를 압축하였다. 코어 레이아웃은 도 12에 도시되어 있다.The outer layer was weighed 75 mg and added to the mold space of a 3/8 "circular concave punch set. The layer was lightly chopped. The inner layer was weighed and added to the chopped outer layer. The granules were lightly chopped. The outer layer 75 mg of was added to the mold space and a 3 ton compression force was applied with a Carver press to compress the triple layer cores.The core layout is shown in FIG.
3 단계 : 약물 방출의 측정Step 3: measuring drug release
2 단계에서 제조된 압축된 코어를 USP 타입 II 기구(UV 분석)를 사용하여 AGF중에서의 약물 방출을 측정하였다. 결과는 도 13에 개시하였다.The compressed cores prepared in
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PCT/US2005/027490 WO2006017537A1 (en) | 2004-08-04 | 2005-08-02 | Sustained drug release composition demonstrating an ascending zero order release pattern, methods of manufacturing such a composition |
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Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080292700A1 (en) * | 1997-04-21 | 2008-11-27 | Biovail Laboratories | Controlled release formulations using intelligent polymers |
US20050232995A1 (en) * | 2002-07-29 | 2005-10-20 | Yam Nyomi V | Methods and dosage forms for controlled delivery of paliperidone and risperidone |
US20050208132A1 (en) * | 2002-07-29 | 2005-09-22 | Gayatri Sathyan | Methods and dosage forms for reducing side effects of benzisozazole derivatives |
US9744137B2 (en) * | 2006-08-31 | 2017-08-29 | Supernus Pharmaceuticals, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
MX2009002336A (en) * | 2006-09-01 | 2009-03-20 | Teva Pharma | Imatinib compositions. |
US8298576B2 (en) | 2006-11-17 | 2012-10-30 | Supernus Pharmaceuticals, Inc. | Sustained-release formulations of topiramate |
MX2009003911A (en) * | 2006-12-04 | 2009-05-28 | Supernus Pharmaceuticals Inc | Enhanced immediate release formulations of topiramate. |
WO2009025859A1 (en) * | 2007-08-21 | 2009-02-26 | Teva Pharmaceutical Industries Ltd. | Paliperidone sustained release formulation |
US20090060983A1 (en) * | 2007-08-30 | 2009-03-05 | Bunick Frank J | Method And Composition For Making An Orally Disintegrating Dosage Form |
WO2009042809A1 (en) * | 2007-09-25 | 2009-04-02 | Teva Pharmaceutical Industries Ltd. | Stable imatinib compositions |
CN101842085B (en) * | 2007-10-31 | 2013-01-30 | 麦克内尔-Ppc股份有限公司 | Orally disintegrated dosage form |
BRPI0906754A2 (en) * | 2008-02-04 | 2015-07-07 | Torrent Pharmaceuticals Ltd | Paliperidone Release Extended Dosage Form |
WO2010009900A1 (en) * | 2008-07-25 | 2010-01-28 | Krka, D.D. Novo Mesto | Paliperidone composition comprising solid matrix particles |
EP2161019A1 (en) * | 2008-09-05 | 2010-03-10 | KRKA, D.D., Novo Mesto | Prolonged release multiparticulate pharmaceutical composition comprising paliperidone |
WO2010044097A2 (en) * | 2008-09-15 | 2010-04-22 | Intas Pharmaceuticals Limited | Novel dosage form of paliperidone and process for preparing the same |
WO2010089775A2 (en) * | 2009-02-05 | 2010-08-12 | Getz Pharma Research | Improved drug dosage form for controlled delivery of one or more pharmaceutically active agent |
WO2011018246A2 (en) | 2009-08-13 | 2011-02-17 | Synthon B.V. | Controlled release paliperidone composition |
US20110052687A1 (en) * | 2009-08-26 | 2011-03-03 | Glenmark Generics Ltd | Extended release pharmaceutical composition of paliperidone |
US8858210B2 (en) | 2009-09-24 | 2014-10-14 | Mcneil-Ppc, Inc. | Manufacture of variable density dosage forms utilizing radiofrequency energy |
US20110070286A1 (en) * | 2009-09-24 | 2011-03-24 | Andreas Hugerth | Process for the manufacture of nicotine-comprising chewing gum and nicotine-comprising chewing gum manufactured according to said process |
US20110070301A1 (en) * | 2009-09-24 | 2011-03-24 | Luber Joseph R | Orally transformable tablets |
US8313768B2 (en) * | 2009-09-24 | 2012-11-20 | Mcneil-Ppc, Inc. | Manufacture of tablet having immediate release region and sustained release region |
EP2485712A1 (en) | 2009-10-06 | 2012-08-15 | Ascendis Pharma A/S | Subcutaneous paliperidone composition |
EP2485767A1 (en) | 2009-10-06 | 2012-08-15 | Ascendis Pharma A/S | Carrier linked paliperidone prodrugs |
US9271939B2 (en) | 2010-03-15 | 2016-03-01 | Inventia Healthcare Private Limited | Stabilized prolonged release pharmaceutical composition comprising atypical antipsychotic |
EP2529756B1 (en) | 2011-05-31 | 2021-05-19 | Laboratorios Farmaceuticos Rovi, S.A. | Risperidone and/or Paliperidone implant formulation |
WO2012014052A2 (en) | 2010-07-30 | 2012-02-02 | Micro Labs Limited | Novel coated extended release pharmaceutical compositions containing paliperidone |
CN102058517A (en) * | 2010-12-31 | 2011-05-18 | 泰州万全医药科技有限公司 | Paliperidone slow release formulation and preparation method thereof |
PL2529757T3 (en) | 2011-05-31 | 2014-04-30 | Farm Rovi Lab Sa | Paliperidone implant formulation |
US20130034605A1 (en) | 2011-08-01 | 2013-02-07 | Micro Labs Limited | Extended release pharmaceutical compositions containing paliperidone |
CN103316026B (en) | 2012-03-23 | 2016-05-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Contain joint product of Phentermine and Topiramate and preparation method thereof |
US9457008B2 (en) | 2012-03-23 | 2016-10-04 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Joint product comprising synephrine and topiramate |
CN102579367B (en) * | 2012-03-23 | 2014-03-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Topiramate sustained-release drug composition, method for preparing same and application of Topiramate sustained-release drug composition |
US9445971B2 (en) | 2012-05-01 | 2016-09-20 | Johnson & Johnson Consumer Inc. | Method of manufacturing solid dosage form |
US9233491B2 (en) | 2012-05-01 | 2016-01-12 | Johnson & Johnson Consumer Inc. | Machine for production of solid dosage forms |
US9511028B2 (en) | 2012-05-01 | 2016-12-06 | Johnson & Johnson Consumer Inc. | Orally disintegrating tablet |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
WO2014167439A1 (en) * | 2013-03-26 | 2014-10-16 | Wockhardt Limited | Modified release pharmaceutical compositions of topiramate or salts thereof |
CN103271889B (en) * | 2013-05-23 | 2015-10-28 | 沈阳药科大学 | Novel paliperidone progressively-increarelease release osmotic pump preparation and preparation method thereof |
CN106068120B (en) | 2014-01-10 | 2021-03-23 | 强生消费者公司 | Method for making tablets using radiofrequency and lossy coated particles |
BR112018071908A2 (en) * | 2016-04-26 | 2019-02-05 | Lts Lohmann Therapie Systeme Ag | film-like administration method for transmucosal release of antidiabetic peptides and method for producing same |
US10493026B2 (en) | 2017-03-20 | 2019-12-03 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
GB201715109D0 (en) * | 2017-09-19 | 2017-11-01 | Johnson Matthey Plc | Release system and method |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2236483B1 (en) * | 1973-07-12 | 1976-11-12 | Choay Sa | |
US4316884A (en) * | 1979-01-25 | 1982-02-23 | Adria Laboratories, Inc. | Sustained release pharmaceutical formulation |
DE3045135A1 (en) * | 1980-11-29 | 1982-06-09 | Sandoz-Patent-GmbH, 7850 Lörrach | BODEGRADABLE POLYMERS CONTAINING PHARMACEUTICAL COMPOSITIONS |
DE3508097A1 (en) * | 1984-07-21 | 1986-02-06 | Hoechst Ag, 6230 Frankfurt | COMBINATION PRODUCT MADE OF XANTHINE DERIVATIVES AND O-ACETYLSALICYL ACID OR THEIR PHARMACOLOGICALLY COMPATIBLE SALTS AND THE USE THEREOF |
EP0230654B1 (en) * | 1985-12-28 | 1992-03-18 | Sumitomo Pharmaceuticals Company, Limited | Sustained pulsewise release pharmaceutical preparation |
AU5741590A (en) * | 1989-05-04 | 1990-11-29 | Southern Research Institute | Improved encapsulation process and products therefrom |
KR930006431B1 (en) * | 1990-10-11 | 1993-07-16 | 재단법인 한국화학연구소 | Microcapsulation of drugs |
IT1256393B (en) * | 1992-11-17 | 1995-12-04 | Inverni Della Beffa Spa | MULTI-LAYER MATERIAL FORMS FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS |
US5407687A (en) * | 1994-02-22 | 1995-04-18 | Glaxo Inc. | Ranitidine solid dosage form |
US5582838A (en) * | 1994-12-22 | 1996-12-10 | Merck & Co., Inc. | Controlled release drug suspension delivery device |
AU4801497A (en) * | 1996-09-30 | 1998-04-24 | Alza Corporation | Dosage form and method for administering drug |
US6919373B1 (en) * | 1996-11-12 | 2005-07-19 | Alza Corporation | Methods and devices for providing prolonged drug therapy |
JP4171091B2 (en) * | 1996-11-15 | 2008-10-22 | 味の素株式会社 | Tablet composition |
US5980942A (en) * | 1997-01-23 | 1999-11-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Zero-order sustained release matrix tablet formulations of carbamazepine |
DE60024320T2 (en) * | 1999-12-28 | 2006-08-10 | Ajinomoto Co., Inc. | ORAL COMPOSITIONS FOR DIABETES |
GB0117618D0 (en) * | 2001-07-19 | 2001-09-12 | Phoqus Ltd | Pharmaceutical dosage form |
ATE373472T1 (en) * | 2002-07-29 | 2007-10-15 | Alza Corp | METHOD AND DOSAGE FORMS FOR THE CONTROLLED DELIVERY OF PALIPERIDONE |
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